Abstract
Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:71–80
The Semaphorin Nomenclature Committee (1999) Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell 97:551–552
Yu HH, Kolodkin AL (1999) Semaphorin signaling: a little less per-plexin. Neuron 22:11–14
Gavert N, Ben-Shmuel A, Raveh S, Ben-Ze’ev A (2008) L1-CAM in cancerous tissues. Expert Opin Biol Ther 8:1749–1757
Schäfer MK, Frotscher M. Role of L1CAM for axon sprouting and branching. Cell Tissue Res. 2012 Feb 28. [Epub ahead of print]
Pellet-Many C, Frankel P, Jia H, Zachary I (2008) Neuropilins: structure, function and role in disease. Biochem J 411:211–226
Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146:233–242
Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745
Yazdani U, Terman JR (2006) The semaphorins. Genome Biol 7:211
Usui H, Taniguchi M, Yokomizo T, Shimizu T (2003) Plexin-A1 and plexin-B1 specifically interact at their cytoplasmic domains. Biochem Biophys Res Commun 300:927–931
Melani M, Weinstein BM (2010) Common factors regulating patterning of the nervous and vascular systems. Annu Rev Cell Dev Biol 26:639–665
Burgess AW (2008) EGFR family: structure physiology signalling and therapeutic targets. Growth Factors 26:263–274
Benvenuti S, Comoglio PM (2007) The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol 213:316–325
Schor NF (2005) The p75 neurotrophin receptor in human development and disease. Prog Neurobiol 77:201–214
Perälä NM, Immonen T, Sariola H (2005) The expression of plexins during mouse embryogenesis. Gene Expr Patterns 5:355–362
van der Zwaag B, Hellemons AJ, Leenders WP, Burbach JP, Brunner HG, Padberg GW, Van Bokhoven H (2002) PLEXIN-D1, a novel plexin family member, is expressed in vascular endothelium and the central nervous system during mouse embryogenesis. Dev Dyn 225:336–343
Roodink I, Verrijp K, Raats J, Leenders WP (2009) Plexin D1 is ubiquitously expressed on tumor vessels and tumor cells in solid malignancies. BMC Cancer 9:297
Worzfeld T, Püschel AW, Offermanns S, Kuner R (2004) Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development. Eur J Neurosci 19:2622–2632
Deng S, Hirschberg A, Worzfeld T, Penachioni JY, Korostylev A, Swiercz JM, Vodrazka P, Mauti O, Stoeckli ET, Tamagnone L, Offermanns S, Kuner R (2007) Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. J Neurosci 27:6333–6347
Zielonka M, Xia J, Friedel RH, Offermanns S, Worzfeld T (2010) A systematic expression analysis implicates Plexin-B2 and its ligand Sema4C in the regulation of the vascular and endocrine system. Exp Cell Res 316:2477–2486
Pasterkamp RJ, Kolk SM, Hellemons AJ, Kolodkin AL (2007) Expression patterns of Semaphorin7A and plexinC1 during rat neural development suggest roles in axon guidance and neuronal migration. BMC Dev Biol 7:98
Mauti O, Sadhu R, Gemayel J, Gesemann M, Stoeckli ET (2006) Expression patterns of plexins and neuropilins are consistent with cooperative and separate functions during neural development. BMC Dev Biol 6:32
Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Björling L, Ponten F (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 28:1248-50. http://www.proteinatlas.org/
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:6062–6067
Ohta K, Mizutani A, Kawakami A, Murakami Y, Kasuya Y, Takagi S, Tanaka H, Fujisawa H (1995) Plexin: a novel neuronal cell surface molecule that mediates cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Neuron 14:1189–1199
Kolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389–1399
Perälä N, Sariola H, Immonen T (2012) More than nervous: the emerging roles of plexins. Differentiation 83:77–91
Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437:169–183
Ayala R, Shu T, Tsai LH (2007) Trekking across the brain: the journey of neuronal migration. Cell 128:29–43
Derijck AA, Van Erp S, Pasterkamp RJ (2010) Semaphorin signaling: molecular switches at the midline. Trends Cell Biol 20:568–576
Chédotal A (2011) Further tales of the midline. Curr Opin Neurobiol 21:68–75
Kolodkin AL, Tessier-Lavigne M (2011) Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb Perspect Biol 3. (pii: a001727)
Waimey KE, Cheng HJ (2006) Axon pruning and synaptic development: how are they per-plexin? Neuroscientist 12:398–409
Bilimoria PM, Bonni A (2011) Molecular regulation of axon branching. Neuroscientist. Dec 15. [Epub ahead of print]
Shen K, Cowan CW (2010) Guidance molecules in synapse formation and plasticity. Cold Spring Harb Perspect Biol 2:a001842
Murakami Y, Suto F, Shimizu M, Shinoda T, Kameyama T, Fujisawa H (2001) Differential expression of plexin-A subfamily members in the mouse nervous system. Dev Dyn 220:246–258
Fujisawa H (2004) Discovery of semaphorin receptors, neuropilin and plexin, and their functions in neural development. J Neurobiol 59:24–33
Gay CM, Zygmunt T, Torres-Vázquez J (2011) Diverse functions for the semaphorin receptor PlexinD1 in development and disease. Dev Biol 349:1–19
Pasterkamp RJ, Giger RJ (2009) Semaphorin function in neural plasticity and disease. Curr Opin Neurobiol 19:263–274
Mauti O, Domanitskaya E, Andermatt I, Sadhu R, Stoeckli ET (2007) Semaphorin6A acts as a gate keeper between the central and the peripheral nervous system. Neural Dev 2:28
Waimey KE, Huang PH, Chen M, Cheng HJ (2008) Plexin-A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors. Dev Biol 315:448–458
Bron R, Vermeren M, Kokot N, Andrews W, Little GE, Mitchell KJ, Cohen J (2007) Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism. Neural Dev 2:21
Renaud J, Kerjan G, Sumita I, Zagar Y, Georget V, Kim D, Fouquet C, Suda K, Sanbo M, Suto F, Ackerman SL, Mitchell KJ, Fujisawa H, Chédotal A (2008) Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells. Nat Neurosci 11:440–449
Suto F, Ito K, Uemura M, Shimizu M, Shinkawa Y, Sanbo M, Shinoda T, Tsuboi M, Takashima S, Yagi T, Fujisawa H (2005) Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 25:3628–3637
Bagri A, Cheng HJ, Yaron A, Pleasure SJ, Tessier-Lavigne M (2003) Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family. Cell 113:285–299
Tran TS, Rubio ME, Clem RL, Johnson D, Case L, Tessier-Lavigne M, Huganir RL, Ginty DD, Kolodkin AL (2009) Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462:1065–1069
Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM (1999) Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99:59–69
Rohm B, Ottemeyer A, Lohrum M, Püschel AW (2010) Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A. Mech Dev 93:95–104
Ben-Zvi A, Manor O, Schachner M, Yaron A, Tessier-Lavigne M, Behar O (2008) The Semaphorin receptor PlexinA3 mediates neuronal apoptosis during dorsal root ganglia development. J Neurosci 28:12427–12432
Yaron A, Huang PH, Cheng HJ, Tessier-Lavigne M (2005) Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins. Neuron 45:513–523
Vodrazka P, Korostylev A, Hirschberg A, Swiercz JM, Worzfeld T, Deng S, Fazzari P, Tamagnone L, Offermanns S, Kuner R (2009) The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. Eur J Neurosci 30:1193–1208
Hirschberg A, Deng S, Korostylev A, Paldy E, Costa MR, Worzfeld T, Vodrazka P, Wizenmann A, Götz M, Offermanns S, Kuner R (2010) Gene deletion mutants reveal a role for semaphorin receptors of the plexin-B family in mechanisms underlying corticogenesis. Mol Cell Biol 30:764–780
Friedel RH, Kerjan G, Rayburn H, Schüller U, Sotelo C, Tessier-Lavigne M, Chédotal A (2007) Plexin-B2 controls the development of cerebellar granule cells. J Neurosci 27:3921–3932
Worzfeld T, Rauch P, Karram K, Trotter J, Kuner R, Offermanns S (2009) Mice lacking Plexin-B3 display normal CNS morphology and behaviour. Mol Cell Neurosci 42:372–381
Artigiani S, Conrotto P, Fazzari P, Gilestro GF, Barberis D, Giordano S, Comoglio PM, Tamagnone L (2004) Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 5:710–714
Li X, Lee AY (2010) Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase. J Biol Chem 285:32436–32445
Li X, Law JW, Lee AY. (2011) Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton. Oncogene. Jun 27. doi: 10.1038/onc.2011.256
Hartwig C, Veske A, Krejcova S, Rosenberger G, Finckh U (2005) Plexin B3 promotes neurite outgrowth, interacts homophilically, and interacts with Rin. BMC Neurosci 6:53
Saito Y, Oinuma I, Fujimoto S, Negishi M (2009) Plexin-B1 is a GTPase-activating protein for M-Ras, remodelling dendrite morphology. EMBO Rep 10:614–621
Xu C, Fan CM (2007) Allocation of paraventricular and supraoptic neurons requires Sim1 function: a role for a Sim1 downstream gene PlexinC1. Mol Endocrinol 21:1234–1245
Pecho-Vrieseling E, Sigrist M, Yoshida Y, Jessell TM, Arber S (2009) Specificity of sensory-motor connections encoded by Sema3e-Plxnd1 recognition. Nature 459:842–846
Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822
Bellon A, Luchino J, Haigh K, Rougon G, Haigh J, Chauvet S, Mann F (2010) VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 66(2):205–219
Ding JB, Oh WJ, Sabatini BL, Gu C (2011) Semaphorin 3E-Plexin-D1 signaling controls pathway-specific synapse formation in the striatum. Nat Neurosci. Dec 18. doi: 10.1038/nn.3003. [Epub ahead of print]
Comoglio PM, Tamagnone L, Giordano S (2004) Invasive growth: a two-way street for semaphorin signalling. Nat Cell Biol 6:1155–1157
Egea J, Klein R (2007) Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol 17:230–238
Schultze W, Eulenburg V, Lessmann V, Herrmann L, Dittmar T, Gundelfinger ED, Heumann R, Erdmann KS (2001) Semaphorin4F interacts with the synapse-associated protein SAP90/PSD-95. J Neurochem 78:482–489
Burkhardt C, Müller M, Badde A, Garner CC, Gundelfinger ED, Püschel AW (2005) Semaphorin 4B interacts with the post-synaptic density protein PSD-95/SAP90 and is recruited to synapses through a C-terminal PDZ-binding motif. FEBS Lett 579:3821–3828
Wang LH, Kalb RG, Strittmatter SM (1999) A PDZ protein regulates the distribution of the transmembrane semaphorin, M-SemF. J Biol Chem 274:14137–14146
Cai H, Reed RR (1999) Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 19:6519–6527
Castellani V, Chédotal A, Schachner M, Faivre-Sarrailh C, Rougon G (2000) Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27:237–249
Castellani V, De Angelis E, Kenwrick S, Rougon G (2002) Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 21:6348–6357
Castellani V, Falk J, Rougon G (2004) Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 26:89–100
Hernández-Miranda LR, Cariboni A, Faux C, Ruhrberg C, Cho JH, Cloutier JF, Eickholt BJ, Parnavelas JG, Andrews WD (2011) Robo1 regulates semaphorin signaling to guide the migration of cortical interneurons through the ventral forebrain. J Neurosci 31:6174–6187
Mann F, Chauvet S, Rougon G (2007) Semaphorins in development and adult brain: implication for neurological diseases. Prog Neurobiol 82:57–79
Yaron A, Zheng B (2007) Navigating their way to the clinic: emerging roles for axon guidance molecules in neurological disorders and injury. Dev Neurobiol 67:1216–1231
Good PF, Alapat D, Hsu A, Chu C, Perl D, Wen X, Burstein DE, Kohtz DS (2004) A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer’s disease. J Neurochem 91:716–736
Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells 10:165–179
Mah S, Nelson MR, Delisi LE, Reneland RH, Markward N, James MR, Nyholt DR, Hayward N, Handoko H, Mowry B, Kammerer S, Braun A (2006) Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Mol Psychiatry 11:471–478
Wray NR, James MR, Mah SP, Nelson M, Andrews G, Sullivan PF, Montgomery GW, Birley AJ, Braun A, Martin NG (2007) Anxiety and comorbid measures associated with PLXNA2. Arch Gen Psychiatry 64:318–326
Fujii T, Uchiyama H, Yamamoto N, Hori H, Tatsumi M, Ishikawa M, Arima K, Higuchi T, Kunugi H (2011) Possible association of the semaphorin 3D gene (SEMA3D) with schizophrenia. J Psychiatr Res 45:47–53
Rünker AE, O’Tuathaigh C, Dunleavy M, Morris DW, Little GE, Corvin AP, Gill M, Henshall DC, Waddington JL, Mitchell KJ (2011) Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology. PLoS ONE 6:e26488
Rujescu D, Meisenzahl EM, Krejcova S, Giegling I, Zetzsche T, Reiser M, Born CM, Möller HJ, Veske A, Gal A, Finckh U (2007) Plexin B3 is genetically associated with verbal performance and white matter volume in human brain. Mol Psychiatry 12:190–194
Lalani SR, Safiullah AM, Molinari LM, Fernbach SD, Martin DM, Belmont JW (2004) SEMA3E mutation in a patient with CHARGE syndrome. J Med Genet 41:e94
Clarimon J, Scholz S, Fung HC, Hardy J, Eerola J, Hellstrom O, Chen CM, Wu YR, Tienari PJ, Singleton A (2006) Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease. Am J Hum Genet 78:1082–1084
Gant JC, Thibault O, Blalock EM, Yang J, Bachstetter A, Kotick J, Schauwecker PE, Hauser KF, Smith GM, Mervis R, Li Y, Barnes GN (2009) Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy. Epilepsia 50:629–645
Formolo CA, Williams R, Gordish-Dressman H, MacDonald TJ, Lee NH, Hathout Y (2011) Secretome signature of invasive glioblastoma multiforme. J Proteome Res 10:3149–3159
Binmadi NO, Yang YH, Zhou H, Proia P, Lin YL, Batista De Paula AM, Sena Guimarães AL, Poswar FO, Sundararajan D, Basile JR (2012) Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner. Am J Pathol. [Epub ahead of print]
de Wit J, Verhaagen J (2003) Role of semaphorins in the adult nervous system. Prog Neurobiol 71:249–267
Sandvig A, Berry M, Barrett LB, Butt A, Logan A (2004) Myelin-, reactive glia-, and scar-derived CNS axon growth inhibitors: expression, receptor signaling, and correlation with axon regeneration. Glia 46:225–251
Pasterkamp RJ, Verhaagen J (2006) Semaphorins in axon regeneration: developmental guidance molecules gone wrong? Philos Trans R Soc Lond B Biol Sci 361:1499–1511
Giger RJ, Hollis ER 2nd, Tuszynski MH (2010) Guidance molecules in axon regeneration. Cold Spring Harb Perspect Biol 2:a001867
McCormick AM, Leipzig ND (2012) Neural regenerative strategies incorporating biomolecular axon guidance signals. Ann Biomed Eng. [Epub ahead of print]
Syed YA, Hand E, Möbius W, Zhao C, Hofer M, Nave KA, Kotter MR (2011) Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci 31:3719–3728
De Winter F, Holtmaat AJ, Verhaagen J (2002) Neuropilin and class 3 semaphorins in nervous system regeneration. Adv Exp Med Biol 515:115–139
Shifman MI, Selzer ME (2007) Differential expression of class 3 and 4 semaphorins and netrin in the lamprey spinal cord during regeneration. J Comp Neurol 501:631–646
Moreau-Fauvarque C, Kumanogoh A, Camand E, Jaillard C, Barbin G, Boquet I, Love C, Jones EY, Kikutani H, Lubetzki C, Dusart I, Chédotal A (2003) The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion. J Neurosci 23:9229–9239
Williams A, Piaton G, Aigrot MS, Belhadi A, Théaudin M, Petermann F, Thomas JL, Zalc B, Lubetzki C (2007) Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain 130:2554–2565
Kotter MR, Stadelmann C, Hartung HP (2011) Enhancing remyelination in disease–can we wrap it up? Brain 134:1882–1900
Okuno T, Nakatsuji Y, Kumanogoh A (2011) The role of immune semaphorins in multiple sclerosis. FEBS Lett 585:3829–3835
Segura I, de Smet F, Hohensinner PJ, Ruiz de Almodovar C, Carmeliet P (2009) The neurovascular link in health and disease: an update. Trends Mol Med 15:439–451
Joyal JS, Sitaras N, Binet F, Rivera JC, Stahl A, Zaniolo K, Shao Z, Polosa A, Zhu T, Hamel D, Djavari M, Kunik D, Honoré JC, Picard E, Zabeida A, Varma DR, Hickson G, Mancini J, Klagsbrun M, Costantino S, Beauséjour C, Lachapelle P, Smith LE, Chemtob S, Sapieha P (2011) Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood 117:6024–6035
Bannerman P, Ara J, Hahn A, Hong L, McCauley E, Friesen K, Pleasure D (2008) Peripheral nerve regeneration is delayed in neuropilin 2-deficient mice. J Neurosci Res 86:3163–3169
Lee JK, Chow R, Xie F, Chow SY, Tolentino KE, Zheng B (2010) Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration. J Neurosci 30:10899–10904
Williams G, Eickholt BJ, Maison P, Prinjha R, Walsh FS, Doherty P (2005) A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists. J Neurochem 92:1180–1190
Montolio M, Messeguer J, Masip I, Guijarro P, Gavin R, Antonio Del Río J, Messeguer A, Soriano E (2009) A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration. Chem Biol 16:691–701
Ziemba KS, Chaudhry N, Rabchevsky AG, Jin Y, Smith GM (2008) Targeting axon growth from neuronal transplants along preformed guidance pathways in the adult CNS. J Neurosci 28:340–348
Long JB, Jay SM, Segal SS, Madri JA (2009) VEGF-A and Semaphorin3A: modulators of vascular sympathetic innervation. Dev Biol 334:119–132
Autiero M, Smet FD, Claes F, Carmeliet P (2005) Role of neural guidance signals in blood vessel navigation. Cardiovasc Res 65:629–638
Carmeliet P, Tessier-Lavigene M (2005) Common mechanisms of nerve and blood vessel wiring. Nature 436:193–200
Raab S, Plate KH (2007) Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 113:607–626
Gelfand MV, Hong SGuC (2009) Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning. Trend Cell Biol 19:99–110
Larrivee B, Freitas C, Suchting S, Brunet I, Eichmann A (2009) Guidance of vascular development: lessons from the nervous system. Circ Res 104:428–441
Adams RH, Eichmann A (2010) Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol 2:a001875
Gitler AD, Lu MM, Epstein JA (2004) PlexinD1 and Semaphorin signaling are required in endothelial cells for cardiovascular development. Dev Cell 7:107–116
Brown CB, Feiner L, Lu MM, Li J, Ma X, Webber AL, Jia L, Raper JA, Epstein JA (2001) PlexinA2 and semaphorin signaling during cardiac neural crest development. Development 128:3071–3080
Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, Takahashi T, Matsuoka R, Yamagishi H (2009) GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci USA 106:13933–13938
Goldmuntz E, Emanuel BS (1997) Genetic disorders of cardiac morphogenesis. The DiGeorge and velocardiofacial syndromes. Circ Res 80:437–443
Kochilas L, Merscher-Gomez S, Lu MM, Potluri V, Liao J, Kucherlapati R, Morrow B, Epstein JA (2002) The role of neural crest during cardiac development in a mouse model of DiGeorge syndrome. Dev Biol 251:157–166
Toyofuku T, Yoshida J, Sugimoto T, Yamamoto M, Makino N, Takamatsu H, Takegahara N, Suto F, Hori M, Fujisawa H, Kumanogoh A, Kikutani H (2008) Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Dev Biol 321:251–262
Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa S, Uemura A (2011) Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J Clin Invest 121:1974–1985
Toyofuku T, Kikutani H (2007) Semaphorins: receptor and intracellular signaling mechanisms, Chapter 9, Semaphorin signaling during cardiac development. Adv Exp Med Biol 600:109–117
Herzog Y, Guttmann-Raviv N, Neufeld G (2005) Segregation of arterial and venous markers in subpopulations of blood islands before vessel formation. Dev Dyn 232:1047–1055
Lamont RE, Lamont EJ, Childs SJ (2009) Antagonistic interactions among plexins regulate the timing of intersegmental vessel formation. Dev Biol 331:199–209
Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J, Aoki K, Yabuki M, Hori M, Fujisawa H, Kikutani H (2004) Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, PlexinA1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 18:435–447
Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Yabuki M, Harada K, Hori M, Kikutani H (2004) Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6:1204–1211
Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268
Torres-Vazquez J, Gitler AD, Fraser SD, Berk JD, Pham VN, Fishman MC, Childs S, Epstein JA, Weinstein BM (2004) Semaphorin-Plexin signaling guides pattering of the developing vasculature. Dev Cell 7:117–123
Kim J, Oh WJ, Gaiano N, Yoshida Y, Gu C (2011) Semaphorin 3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism. Genes Dev 25:1399–1411
Zygmunt T, Gay CM, Blondelle J, Singh MK, Flaherty KM, Means PC, Herwig L, Krudewig A, Belting HG, Affolter M, Epstein JA, Torres-Vázquez J (2011) Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev Cell 21:301–314
Jiang SX, Sheldrick M, Desbois A, Slinn J, Hou ST (2007) Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo. Mol Cell Biol 27:1696–1705
Whitehead SN, Gangaraju S, Slinn J, Hou ST (2010) Transient and bilateral increase in Neuropilin-1, Fer kinase and collapsin response mediator proteins within membrane rafts following unilateral occlusion of the middle cerebral artery in mouse. Brain Res 1344:209–216
Rogalewski A, Dittgen T, Klugmann M, Kirsch F, Kruger C, Pitzer C, Minnerup J, Schabitz WR, Schneider A (2010) Semaphorin 6A improves functional recovery in conjunction with motor training after cerebral ischemia. PLoS ONE 5:e10737
Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Fan R, Boumsell L, Kumanogoh A, Kikutani H, Tamagnone L, Wagner DD, Milla ME, Brass LF (2007) Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci 104:1621–1626
Kumar I, Staton CA, Cross SS, Reed MW, Brown NJ (2009) Angiogenesis, vascular endothelial growth factor and its receptors in human surgical wounds. Br J Surg 96:1484–1491
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Neufeld G, Lange T, Varshavsky A, Kessler O (2007) Semaphorin signaling in vascular and tumor biology. Adv Exp Med Biol 600:118–131
Chédotal A, Kerjan G, Moreau-Fauvarque C (2005) The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ 12:1044–1056
Capparuccia L, Tamagnone L (2009) Semaphorin signaling in cancer cells and in cells of the tumor microenvironment–two sides of a coin. J Cell Sci 122:1723–1736
Staton CA (2011) Class 3 semaphorins and their receptors in physiological and pathological angiogenesis. Biochem Soc Trans 39:1565–1570
Micucci C, Orciari S, Catalano A (2010) Semaphorins and their receptors in stem and cancer cells. Curr Med Chem 17:3462–3475
Sakurai A, Doci C, Gutkind JS (2012) Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res 22:23–32
Neufeld G, Sabag AD, Rabinovicz N, Kessler O (2012) Semaphorins in angiogenesis and tumor progression. Cold Spring Harb Perspect Med. 2(1):a006718
Muratori C, Tamagnone L (2012) Semaphorin signals tweaking the tumor microenvironment. Adv Cancer Res 114:59–85
Stuttfeld E, Ballmer-Hofer K (2009) Structure and function of VEGF receptors. IUBMB Life 61:915–922
Casazza A, Fu X, Johansson I, Capparuccia L, Andersson F, Giustacchini A, Squadrito ML, Venneri MA, Mazzone M, Larsson E, Carmeliet P, De Palma M, Naldini L, Tamagnone L, Rolny C (2011) Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler Thromb Vasc Biol 31:741–749
Gabrovska PN, Smith RA, Tiang T, Weinstein SR, Haupt LM, Griffiths LR (2011) Semaphorin-plexin signalling genes associated with human breast tumourigenesis. Gene 489:63–69
Balakrishnan A, Penachioni JY, Lamba S, Bleeker FE, Zanon C, Rodolfo M, Vallacchi V, Scarpa A, Felicioni L, Buck M, Marchetti A, Comoglio PM, Bardelli A, Tamagnone L (2009) Molecular profiling of the “plexinome” in melanoma and pancreatic cancer. Hum Mutat 30:1167–1174
Staton CA, Shaw LA, Valluru M, Hoh L, Koay I, Cross SS, Reed MW, Brown NJ (2011) Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology 59:274–282
Catalano A, Lazzarini R, Di Nuzzo S, Orciari S, Procopio A (2009) The plexin-A1 receptor activates vascular endothelial growth factor-receptor 2 and nuclear factor-kappaB to mediate survival and anchorage-independent growth of malignant mesothelioma cells. Cancer Res 69:1485–1493
Kigel B, Rabinowicz N, Varshavsky A, Kessler O, Neufeld G (2011) Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118:4285–4296
Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM (2002) The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4:720–724
Rody A, Holtrich U, Gaetje R, Gehrmann M, Engels K, von Minckwitz G, Loibl S, Diallo-Danebrock R, Ruckhäberle E, Metzler D, Ahr A, Solbach C, Karn T, Kaufmann M (2007) Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin B1. Clin Cancer Res 13:1115–1122
Rody A, Karn T, Ruckhäberle E, Hanker L, Metzler D, Müller V, Solbach C, Ahr A, Gätje R, Holtrich U, Kaufmann M (2009) Loss of Plexin B1 is highly prognostic in low proliferating ER positive breast cancers—results of a large-scale microarray analysis. Eur J Cancer 45:405–413
Lu TP, Tsai MH, Lee JM, Hsu CP, Chen PC, Lin CW, Shih JY, Yang PC, Hsiao CK, Lai LC, Chuang EY (2010) Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomarkers Prev 19:2590–2597
Ye S, Hao X, Zhou T, Wu M, Wei J, Wang Y, Zhou L, Jiang X, Ji L, Chen Y, You L, Zhang Y, Xu G, Zhou J, Ma D, Wang S (2010) Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion. BMC Cancer 10:611
Argast GM, Croy CH, Couts KL, Zhang Z, Litman E, Chan DC, Ahn NG (2009) Plexin B1 is repressed by oncogenic B-Raf signaling and functions as a tumor suppressor in melanoma cells. Oncogene 28:2697–2709
Basile JR, Castilho RM, Williams VP, Gutkind JS (2006) Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci USA 103:9017–9022
Rieger J, Wick W, Weller M (2003) Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins. Glia 42:379–389
Kato S, Kubota K, Shimamura T, Shinohara Y, Kobayashi N, Watanabe S, Yoneda M, Inamori M, Nakamura F, Ishiguro H, Nakaigawa N, Nagashima Y, Taguri M, Kubota Y, Goshima Y, Morita S, Endo I, Maeda S, Nakajima A, Nakagama H (2011) Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer. Cancer Sci 102:2029–2037
Ch’ng ES, Kumanogoh A (2010) Roles of Sema4D and Plexin-B1 in tumor progression. Mol Cancer 9:251
Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, Bott SR, Nariculam J, Box G, Munson P, Constantinou J, Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A, Masters JR, Williamson M (2007) Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci USA 104:19040–19045
Tong Y, Hota PK, Hamaneh MB, Buck M (2008) Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain. Structure 16:246–258
Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274
Swiercz JM, Worzfeld T, Offermanns S (2009) Semaphorin 4D signaling requires the recruitment of phospholipase C gamma into the plexin-B1 receptor complex. Mol Cell Biol 29:6321–6334
Worzfeld T, Swiercz JM, Looso M, Straub BK, Sivaraj KK, Offermanns S (2012) ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J Clin Invest. 122(4):1296–1305
Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64:5212–5224
Zhou H, Binmadi NO, Yang YH, Proia P, Basile JR (2012) Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression. Angiogenesis Apr 3. [Epub ahead of print]
Lazova R, Gould Rothberg BE, Rimm D, Scott G (2009) The semaphorin 7A receptor Plexin C1 is lost during melanoma metastasis. Am J Dermatopathol 31:177–181
Scott GA, McClelland LA, Fricke AF, Fender A (2009) Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression. J Invest Dermatol 129:954–963
Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10:9–22
Roodink I, Raats J, van der Zwaag B, Verrijp K, Kusters B, van Bokhoven H, Linkels M, de Waal RM, Leenders WP (2005) Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy? Cancer Res 65:8317–8323
Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh A, Hori M (2007) Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. EMBO J 26:1373–1384
Blanc V, Nariculam J, Munson P, Freeman A, Klocker H, Masters J, Williamson M (2011) A role for class 3 semaphorins in prostate cancer. Prostate 71:649–658
Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, Schneider M, Mazzone M, Comoglio PM, Tamagnone L (2010) Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 120:2684–2698
Goshima Y, Ito T, Sasaki Y, Nakamura F (2002) Semaphorins as signals for cell repulsion and invasion. J Clin Invest 109:993–998
Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y, Kessler O (2005) Semaphorins in cancer. Front Biosci 10:751–760
Koch S (2012) Neuropilin signalling in angiogenesis. Biochem Soc Trans 40:20–25
Rizzolio S, Tamagnone L (2011) Multifaceted role of neuropilins in cancer. Curr Med Chem 18:3563–3575
Serini G, Maione F, Giraudo E, Bussolino F (2009) Semaphorins and tumor angiogenesis. Angiogenesis 12:187–193
Roth L, Koncina E, Satkauskas S, Crémel G, Aunis D, Bagnard D (2009) The many faces of semaphorins: from development to pathology. Cell Mol Life Sci 66:649–666
Geretti E, Klagsbrun M (2007) Neuropilins: novel targets for anti-angiogenesis therapies. Cell Adh Migr 1:56–61
Grünewald FS, Prota AE, Giese A, Ballmer-Hofer K (2010) Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta 1804:567–580
Bagri A, Tessier-Lavigne M, Watts RJ (2009) Neuropilins in tumor biology. Clin Cancer Res 15:1860–1864
Iyer S, Darley PI, Acharya KR (2010) Structural insights into the binding of vascular endothelial growth factor-B by VEGFR-1(D2): recognition and specificity. J Biol Chem 285:23779–23789
Leppänen VM, Prota AE, Jeltsch M, Anisimov A, Kalkkinen N, Strandin T, Lankinen H, Goldman A, Ballmer-Hofer K, Alitalo K (2010) Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci USA 107:2425–2430
Leppänen VM, Jeltsch M, Anisimov A, Tvorogov D, Aho K, Kalkkinen N, Toivanen P, Ylä-Herttuala S, Ballmer-Hofer K, Alitalo K (2011) Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Blood 117:1507–1515
Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC (2011) VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation. Mol Biol Cell 22:2766–2776
Vander Kooi CW, Jusino MA, Perman B, Neau DB, Bellamy HD, Leahy DJ (2007) Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci USA 104:6152–6157
Appleton BA, Wu P, Maloney J, Yin J, Liang WC, Stawicki S, Mortara K, Bowman KK, Elliott JM, Desmarais W, Bazan JF, Bagri A, Tessier-Lavigne M, Koch AW, Wu Y, Watts RJ, Wiesmann C (2007) Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J 26:4902–4912
Parker MW, Xu P, Li X, Vander Kooi CW (2012) Structural basis for the selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1. J Biol Chem [Epub ahead of print]
Adams RH, Lohrum M, Klostermann A, Betz H, Püschel AW (1997) The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J 16:6077–6086
Parker MW, Hellman LM, Xu P, Fried MG, Vander Kooi CW (2010) Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry 49:4068–4075
Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G, Tamagnone L (2012) Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med 4(3):234–250
Giordano RJ, Anobom CD, Cardó-Vila M, Kalil J, Valente AP, Pasqualini R, Almeida FC, Arap W (2005) Structural basis for the interaction of a vascular endothelial growth factor mimic peptide motif and its corresponding receptors. Chem Biol 12:1075–1083
Giordano RJ, Cardó-Vila M, Salameh A, Anobom CD, Zeitlin BD, Hawke DH, Valente AP, Almeida FC, Nör JE, Sidman RL, Pasqualini R, Arap W (2010) From combinatorial peptide selection to drug prototype (I): targeting the vascular endothelial growth factor receptor pathway. Proc Natl Acad Sci USA 107:5112–5117
Grothey A, Ellis LM (2008) Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies. Cancer J 14:170–177
Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R, Chapman C, Hartzoulakis B, Nally J, Stewart M, Cheng L, Menon M, Tickner M, Djordjevic S, Driscoll PC, Zachary I, Selwood DL (2010) Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem 53:2215–2226
Loges S, Mazzone M, Hohensinner P, Carmeliet P (2009) Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15:167–170
Ueyama H, Horibe T, Nakajima O, Ohara K, Kohno M, Kawakami K (2011) Semaphorin 3A lytic hybrid peptide binding to neuropilin-1 as a novel anti-cancer agent in pancreatic cancer. Biochem Biophys Res Commun 414:60–66
Cébe-Suarez S, Grünewald FS, Jaussi R, Li X, Claesson-Welsh L, Spillmann D, Mercer AA, Prota AE, Ballmer-Hofer K (2008) Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR. FASEB J 22:3078–3086
Novoa A, Pellegrini-Moïse N, Bechet D, Barberi-Heyob M, Chapleur Y (2010) Sugar-based peptidomimetics as potential inhibitors of the vascular endothelium growth factor binding to neuropilin-1. Bioorg Med Chem 18:3285–3298
Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, Kowalski J, Ho C, Reslan HB, Ross J, Berry L, Kasman I, Zlot C, Cheng Z, Le Couter J, Filvaroff EH, Plowman G, Peale F, French D, Carano R, Koch AW, Wu Y, Watts RJ, Tessier-Lavigne M, Bagri A (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13:331–342
Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, Ross S, Cheng Z, Le Couter J, Plowman G, Peale F, Koch AW, Wu Y, Bagri A, Tessier-Lavigne M, Watts RJ (2007) Blocking neuropilin-1 function has an additive effect with anti- VEGF to inhibit tumor growth. Cancer Cell 11:53–67
Geretti E, van Meeteren LA, Shimizu A, Dudley AC, Claesson-Welsh L, Klagsbrun M (2010) A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol Cancer Res 8:1063–1073
Jubb AM, Strickland LA, Liu SD, Mak J, Schmidt M, Koeppen H (2011) Neuropilin-1 expression in cancer and development. J Pathol 226(1):50–60
Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, Sotiropoulou PA, Loges S, Lapouge G, Candi A, Mascre G, Drogat B, Dekoninck S, Haigh JJ, Carmeliet P, Blanpain C (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478:399–403
Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Crémel G, Hubert P, Bagnard D (2008) Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell 19:646–654
Nasarre C, Roth M, Jacob L, Roth L, Koncina E, Thien A, Labourdette G, Poulet P, Hubert P, Crémel G, Roussel G, Aunis D, Bagnard D (2010) Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene 29:2381–2392
Fantin A, Schwarz Q, Davidson K, Normando EM, Denti L, Ruhrberg C (2011) The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins. Development 138:4185–4191
Zachary IC (2011) How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns. Biochem Soc Trans 39:1583–1591
Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM (1996) A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci USA 93:674–678
Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292
Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289–300
Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S (2005) Sema4D induces angiogenesis through Met recruitment by plexin B1. Blood 105:4321–4329
Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S (2004) Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 23:5131–5137
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925
Corso S, Comoglio PM, Giordano S (2005) Cancer therapy: can the challenge be MET? Trends Mol Med 11:284–292
Soong J, Chen Y, Shustef EM, Scott GA (2012) Sema4D, the Ligand for Plexin B1, Suppresses c- Met Activation and Migration and Promotes Melanocyte Survival and Growth. J Invest Dermatol. 132(4):1230–1238
Stevens L, McClelland L, Fricke A, Williamson M, Kuo I, Scott G (2010) Plexin B1 suppresses c-Met in melanoma: a role for plexin B1 as a tumor-suppressor protein through regulation of c-Met. J Invest Dermatol 130:1636–1645
Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O’Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I (2008) c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations. J Biol Chem 283:2675–2683
Ma PC, Kijima T, Maulik G, Fox EA, Sattler M, Griffin JD, Johnson BE, Salgia R (2003) c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 63:6272–6281
Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E, Giordano S, Corso S, Rolland-Valognes G, Lockhart BP, Hickman JA, Comoglio PM, Trusolino L (2009) Only a subset of Met-activated pathways are required to sustain oncogene addiction. Sci Signal 2:ra80
Follenzi A, Bakovic S, Gual P, Stella MC, Longati P, Comoglio PM (2000) Cross-talk between the proto-oncogenes Met and Ron. Oncogene 19:3041–3049
Bertotti A, Comoglio PM (2003) Tyrosine kinase signal specificity: lessons from the HGF receptor. Trends Biochem Sci 28:527–533
Zhang S, Zhau HE, Osunkoya AO, Iqbal S, Yang X, Fan S, Chen Z, Wang R, Marshall FF, Chung LW, Wu D (2010) Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. Mol Cancer 9:9
Sulpice E, Plouët J, Bergé M, Allanic D, Tobelem G, Merkulova-Rainon T (2008) Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111:2036–2045
Tolbert WD, Daugherty J, Gao C, Xie Q, Miranti C, Gherardi E, Woude GV, Xu HE (2007) A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist. Proc Natl Acad Sci USA 104:14592–14597
Holmes O, Pillozzi S, Deakin JA, Carafoli F, Kemp L, Butler PJ, Lyon M, Gherardi E (2007) Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains. J Mol Biol 367:395–408
Gherardi E, Sandin S, Petoukhov MV, Finch J, Youles ME, Ofverstedt LG, Miguel RN, Blundell TL, Vande Woude GF, Skoglund U, Svergun DI (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA 103:4046–4051
Sun T, Krishnan R, Swiercz JM (2012) Grb2 mediates Semaphorin4D-dependent RhoA inactivation. J Cell Sci. (in press)
Franco M, Tamagnone L (2008) Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Rep 9:865–871
Swiercz JM, Kuner R, Offermanns S (2004) Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 165:869–880
Swiercz JM, Worzfeld T, Offermanns S (2008) ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem 283:1893–1901
Felding-Habermann B (2003) Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20:203–213
Serini G, Napione L, Arese M, Bussolino F (2008) Besides adhesion: new perspectives of integrin functions in angiogenesis. Cardiovasc Res 78:213–222
Basile JR, Gavard J, Gutkind JS (2007) Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem 282:34888–34895
Franco M, Muratori C, Corso S, Tenaglia E, Bertotti A, Capparuccia L, Trusolino L, Comoglio PM, Tamagnone L (2010) The tetraspanin CD151 is required for Met-dependent signaling and tumor cell growth. J Biol Chem 285:38756–38764
Scott GA, McClelland LA, Fricke AF (2008) Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins. J Invest Dermatol 128:151–161
Martin TJ, Sims NA (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med 11:76–81
Gomez C, Burt-Pichat B, Mallein-Gerin F, Merle B, Delmas PD, Skerry TM, Vico L, Malaval L, Chenu C (2005) Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation. Dev Dyn 234:393–403
Takegahara N, Takamatsu H, Toyofuku T, Tsujimura T, Okuno T, Yukawa K, Mizui M, Yamamoto M, Prasad DV, Suzuki K, Ishii M, Terai K, Moriya M, Nakatsuji Y, Sakoda S, Sato S, Akira S, Takeda K, Inui M, Takai T, Ikawa M, Okabe M, Kumanogoh A, Kikutani H (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8:615–622
Ford JW, McVicar DW (2009) TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 21:38–46
Hwang JY, Lee JY, Park MH, Kim KS, Kim KK, Ryu HJ, Lee JK, Han BG, Kim JW, Oh B, Kimm K, Park BL, Shin HD, Kim TH, Hong JM, Park EK, Kim DJ, Koh JM, Kim GS, Kim SY (2006) Association of PLXNA2 polymorphisms with vertebral fracture risk and bone mineral density in postmenopausal Korean population. Osteoporos Int 17:1592–1601
Delorme G, Saltel F, Bonnelye E, Jurdic P, Machuca-Gayet I (2005) Expression and function of semaphorin 7A in bone cells. Biol Cell 97:589–597
Kanda T, Yoshida Y, Izu Y, Nifuji A, Ezura Y, Nakashima K, Noda M (2007) PlexinD1 deficiency induces defects in axial skeletal morphogenesis. J Cell Biochem 101:1329–1337
Zhang Y, Singh MK, Degenhardt KR, Lu MM, Bennett J, Yoshida Y, Epstein JA (2009) Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects. Dev Biol 325:82–93
Okubo M, Kimura T, Fujita Y, Mochizuki S, Niki Y, Enomoto H, Suda Y, Toyama Y, Okada Y (2011) Semaphorin 3A is expressed in human osteoarthritic cartilage and antagonizes vascular endothelial growth factor 165-promoted chondrocyte migration: an implication for chondrocyte cloning. Arthritis Rheum 63:3000–3009
Hayashi M, Nakashima T, Taniguchi M, Kodama T, Kumanogoh A, Takayanagi H- (2012) Osteoprotection by semaphorin 3A. Nature. Apr 18. doi: 10.1038/nature11000
Sutton AL, Zhang X, Dowd DR, Kharode YP, Komm BS, Macdonald PN (2008) Semaphorin 3B is a 1,25-Dihydroxyvitamin D3-induced gene in osteoblasts that promotes osteoclastogenesis and induces osteopenia in mice. Mol Endocrinol 22:1370–1381
Lallier TE (2004) Semaphorin profiling of periodontal fibroblasts and osteoblasts. J Dent Res 83:677–682
Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, Takayanagi H (2011) Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med 17:1473–1480
Dacquin R, Domenget C, Kumanogoh A, Kikutani H, Jurdic P, Machuca-Gayet I (2011) Control of bone resorption by semaphorin 4D is dependent on ovarian function. PLoS ONE 6:e26627
Takimoto A, Nishizaki Y, Hiraki Y, Shukunami C (2009) Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation. Dev Biol 332:196–211
Thi MM, Suadicani SO, Spray DC (2010) Fluid flow-induced soluble vascular endothelial growth factor isoforms regulate actin adaptation in osteoblasts. J Biol Chem 285:30931–30941
Handa A, Tokunaga T, Tsuchida T, Lee YH, Kijima H, Yamazaki H, Ueyama Y, Fukuda H, Nakamura M (2000) Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int J Oncol 17:291–295
Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA (2008) Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87:107–118
Mayr-Wohlfart U, Waltenberger J, Hausser H, Kessler S, Günther KP, Dehio C, Puhl W, Brenner RE (2002) Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone 30:472–477
Belaid-Choucair Z, Lepelletier Y, Poncin G, Thiry A, Humblet C, Maachi M, Beaulieu A, Schneider E, Briquet A, Mineur P, Lambert C, Mendes-Da-Cruz D, Ahui ML, Asnafi V, Dy M, Boniver J, Nusgens BV, Hermine O, Defresne MP (2008) Human bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition. Stem Cells 26:1556–1564
Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, O’Brien S, Kantarjian HM, Cortes JE, Koivunen E, Arap W, Pasqualini R (2011) Targeting neuropilin-1 in human leukemia and lymphoma. Blood 117:920–927
Schuch G, Machluf M, Bartsch G Jr, Nomi M, Richard H, Atala A, Soker S (2002) In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 100:4622–4628
Kong JS, Yoo SA, Kim JW, Yang SP, Chae CB, Tarallo V, De Falco S, Ryu SH, Cho CS, Kim WU (2010) Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis. Arthr Rheum 62:179–190
Takamatsu H, Okuno T, Kumanogoh A (2010) Regulation of immune cell responses by semaphorins and their receptors. Cell Mol Immunol 7:83–88
Mizui M, Kumanogoh A, Kikutani H (2009) Immune semaphorins: novel features of neural guidance molecules. J Clin Immunol 29:1–11
Suzuki K, Kumanogoh A, Kikutani H (2008) Semaphorins and their receptors in immune cell interactions. Nat Immunol 9:17–23
Takamatsu H, Kumanogoh A (2012) Diverse roles for semaphorin-plexin signaling in the immunesystem. Trends Immunol 33(3):127–135
Tran-Van H, Avota E, Börtlein C, Mueller N, Schneider-Schaulies S (2011) Measles virus modulates dendritic cell/T-cell communication at the level of plexinA1/neuropilin-1 recruitment and activity. Eur J Immunol 41:151–163
O’Connor BP, Ting JP (2008) The evolving role of semaphorins and plexins in the immune system: Plexin-A1 regulation of dendritic cell function. Immunol Res 41:217–222
Takamatsu H, Takegahara N, Nakagawa Y, Tomura M, Taniguchi M, Friedel RH, Rayburn H, Tessier-Lavigne M, Yoshida Y, Okuno T, Mizui M, Kang S, Nojima S, Tsujimura T, Nakatsuji Y, Katayama I, Toyofuku T, Kikutani H, Kumanogoh A (2010) Semaphorins guide the entry of dendritic cells into the lymphatics by activating myosin II. Nat Immunol 11:594–600
Lepelletier Y, Smaniotto S, Hadj-Slimane R, Villa-Verde DM, Nogueira AC, Dardenne M, Hermine O, Savino W (2007) Control of human thymocyte migration by neuropilin-1/semaphorin-3A-mediated interactions. Proc Natl Acad Sci USA 104:5545–5550
Yamamoto M, Suzuki K, Okuno T, Ogata T, Takegahara N, Takamatsu H, Mizui M, Taniguchi M, Chédotal A, Suto F, Fujisawa H, Kumanogoh A, Kikutani H (2008) Plexin-A4 negatively regulates T lymphocyte responses. Int Immunol 20:413–420
Wen H, Lei Y, Eun SY, Ting JP (2010) Plexin-A4-semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J Exp Med 207:2943–2957
Granziero L, Circosta P, Scielzo C, Frisaldi E, Stella S, Geuna M, Giordano S, Ghia P, Caligaris-Cappio F (2003) CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5 + B lymphocytes. Blood 101:1962–1969
Chabbert-de Ponnat I, Marie-Cardine A, Pasterkamp RJ, Schiavon V, Tamagnone L, Thomasset N, Bensussan A, Boumsell L (2005) Soluble CD100 functions on human monocytes and immature dendritic cells require plexin C1 and plexin B1, respectively. Int Immunol 17:439–447
Walzer T, Galibert L, Comeau MR, De Smedt T (2005) Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration. J Immunol 174:51–59
Holl EK, O’Connor BP, Holl TM, Roney KE, Zimmermann AG, Jha S, Kelsoe G, Ting JP (2011) Plexin-D1 is a novel regulator of germinal centers and humoral immune responses. J Immunol 186:5603–5611
Choi YI, Duke-Cohan JS, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL (2008) PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. Immunity 29(6):888–898
Catalano A, Caprari P, Moretti S, Faronato M, Tamagnone L, Procopio A (2006) Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107:3321–3329
Kumanogoh A, Shikina T, Suzuki K, Uematsu S, Yukawa K, Kashiwamura S, Tsutsui H, Yamamoto M, Takamatsu H, Ko-Mitamura EP, Takegahara N, Marukawa S, Ishida I, Morishita H, Prasad DV, Tamura M, Mizui M, Toyofuku T, Akira S, Takeda K, Okabe M, Kikutani H (2005) Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22:305–316
Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch’ng E, Ishida I, Fujimura H, Sakoda S, Yoshida K, Kikutani H (2002) Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419:629–633
Nakagawa Y, Takamatsu H, Okuno T, Kang S, Nojima S, Kimura T, Kataoka TR, Ikawa M, Toyofuku T, Katayama I, Kumanogoh A (2011) Identification of semaphorin 4B as a negative regulator of basophil-mediated immune responses. J Immunol 186:2881–2888
Hall KT, Boumsell L, Schultze JL, Boussiotis VA, Dorfman DM, Cardoso AA, Bensussan A, Nadler LM, Freeman GJ (1996) Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. Proc Natl Acad Sci USA 93:11780–11785
Herold C, Elhabazi A, Bismuth G, Bensussan A, Boumsell L (1996) CD100 is associated with CD45 at the surface of human T lymphocytes. Role in T cell homotypic adhesion. J Immunol 157:5262–5268
Delaire S, Billard C, Tordjman R, Chédotal A, Elhabazi A, Bensussan A, Boumsell L (2001) Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol 166:4348–4354
Wang X, Kumanogoh A, Watanabe C, Shi W, Yoshida K, Kikutani H (2001) Functional soluble CD100/Sema4D released from activated lymphocytes: possible role in normal and pathologic immune responses. Blood 97:3498–3504
Shi W, Kumanogoh A, Watanabe C, Uchida J, Wang X, Yasui T, Yukawa K, Ikawa M, Okabe M, Parnes JR, Yoshida K, Kikutani H (2000) The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13:633–642
Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara N, Toyofuku T, Nakagawa Y, Kang S, Friedel RH, Sakoda S, Kikutani H, Kumanogoh A (2010) Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 184:1499–1506
Ishida I, Kumanogoh A, Suzuki K, Akahani S, Noda K, Kikutani H (2003) Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int Immunol 15:1027–1034
Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki H, Hirata H, Iwahori K, Uchida J, Yasui T, Matsumoto M, Yoshida K, Yakura H, Pan C, Parnes JR, Kikutani H (2000) Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13:621–631
O’Connor BP, Eun SY, Ye Z, Zozulya AL, Lich JD, Moore CB, Iocca HA, Roney KE, Holl EK, Wu QP, van Deventer HW, Fabry Z, Ting JP (2008) Semaphorin 6D regulates the late phase of CD4 + T cell primary immune responses. Proc Natl Acad Sci USA 105:13015–13020
Suzuki K, Okuno T, Yamamoto M, Pasterkamp RJ, Takegahara N, Takamatsu H, Kitao T, Takagi J, Rennert PD, Kolodkin AL, Kumanogoh A, Kikutani H (2007) Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 446:680–684
Tordjman R, Lepelletier Y, Lemarchandel V, Cambot M, Gaulard P, Hermine O, Roméo PH (2002) A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat Immunol 3:477–482
Good MC, Zalatan JG, Lim WA (2011) Scaffold proteins: hubs for controlling the flow of cellular information. Science 332:680–686
Kiel C, Yus E, Serrano L (2010) Engineering signal transduction pathways. Cell 140:33–47
Jordan JD, Landau EM, Iyengar R (2000) Signaling networks: the origins of cellular multitasking. Cell 103:193–200
Scott JD, Pawson T (2009) Cell signaling in space and time: where proteins come together and when they’re apart. Science 326:1220–1224
Ridley AJ (2011) Life at the leading edge. Cell 145:1012–1022
Casazza A, Fazzari P, Tamagnone L (2007) Semaphorin signals in cell adhesion and cell migration: functional role and molecular mechanisms. Adv Exp Med Biol 600:90–108
Zhou Y, Gunput RA, Pasterkamp RJ (2008) Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 33:161–170
Vetter IR, Wittinghofer A (2001) The guanine nucleotide-binding switch in three dimensions. Science 294:1299–1304
Hall A, Lalli G (2010) Rho and Ras GTPases in axon growth, guidance, and branching. Cold Spring Harb Perspect Biol 2:a001818
Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877
van Dam TJ, Bos JL, Snel B (2011) Evolution of the Ras-like small GTPases and their regulators. Small GTPases 2:4–16
Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635
Ye X, Carew TJ (2010) Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins. Neuron 68:340–361
Boettner B, Van Aelst L (2002) The role of Rho GTPases in disease development. Gene 286:155–174
Benarroch EE (2007) Rho GTPases: role in dendrite and axonal growth, mental retardation, and axonal regeneration. Neurology 68:1315
Chardin P (2006) Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol 7:54–62
Nobes CD, Lauritzen I, Mattei MG, Paris S, Hall A, Chardin P (1998) A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion. J Cell Biol 141:187–197
Ishikawa Y, Katoh H, Negishi M (2006) Small GTPase Rnd1 is involved in neuronal activity dependentdendritic development in hippocampal neurons. Neurosci Lett 400:218–223
Ishikawa Y, Katoh H, Negishi M (2003) A role of Rnd1 GTPase in dendritic spine formation in hippocampal neurons. J Neurosci 23:11065–11072
Harada A, Katoh H, Negishi M (2005) Direct interaction of Rnd1 with FRS2 beta regulates Rnd1-induced down-regulation of RhoA activity and is involved in fibroblast growth factor-induced neurite outgrowth in PC12 cells. J Biol Chem 280:18418–18424
Katoh H, Harada A, Mori K, Negishi M (2002) Socius is a novel Rnd GTPase-interacting protein involved in disassembly of actin stress fibers. Mol Cell Biol 22:2952–2964
Li YH, Ghavampur S, Bondallaz P, Will L, Grenningloh G, Püschel AW (2009) Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10. J Biol Chem 284:363–371
Vikis HG, Li W, Guan KL (2002) The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Genes Dev 16:836–845
Zanata SM, Hovatta I, Rohm B, Püschel AW (2002) Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse. J Neurosci 22:471–477
Oinuma I, Katoh H, Harada A, Negishi M (2003) Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells. J Biol Chem 278:25671–25677
Hu H, Marton TF, Goodman CS (2001) Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 32:39–51
Negishi M, Buck M (2012) “Ras/Rap GAP function and GTPase sequestration in plexin-mediated cell signaling mechanisms” Commentary/E-letter in Science Signaling http://stke.sciencemag.org/cgi/eletters/5/207/ra6
Vikis HG, Li W, He Z, Guan KL (2000) The semaphorin receptor plexin-B1 specifically interacts with active Rac in a ligand-dependent manner. Proc Natl Acad Sci USA 97:12457–12462
Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Shen L, Park HW, Buck M (2007) Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem 282:37215–37224
Uesugi K, Oinuma I, Katoh H, Negishi M (2009) Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1. J Biol Chem 284:6743–6751
Hota PK, Buck M (2009) Thermodynamic characterization of two homologous protein complexes: associations of the semaphorin receptor plexin-B1 RhoGTPase binding domain with Rnd1 and active Rac1. Protein Sci 18:1060–1071
Wang H, Hota PK, Tong Y, Li B, Shen L, Nedyalkova L, Borthakur S, Kim S, Tempel W, Buck M, Park HW (2011) Structural basis of Rnd1 binding to plexin Rho GTPase binding domains (RBDs). J Biol Chem 286:26093–26106
Zhou C, Wong OG, Masters JR, Williamson M (2012) Effect of cancer-associated mutations in the PlexinB1 gene. Mol Cancer 11:11
Toyofuku T, Yoshida J, Sugimoto T, Zhang H, Kumanogoh A, Hori M, Kikutani H (2005) FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 8:1712–1719
Püschel AW (2007) GTPases in semaphorin signaling. Adv Exp Med Biol 600:12–23
Turner LJ, Nicholls S, Hall A (2004) The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem 279:33199–33205
Bar-Sagi D, Hall A (2000) Ras and Rho GTPases: a family reunion. Cell 103:227–238
Kinbara K, Goldfinger LE, Hansen M, Chou FL, Ginsberg MH (2003) Ras GTPases: integrins’ friends or foes? Nat Rev Mol Cell Biol 4:767–776
Rohm B, Rahim B, Kleiber B, Hovatta I, Püschel AW (2000) The semaphorin 3A receptor may directly regulate the activity of small GTPases. FEBS Lett 486:68–72
Oinuma I, Ishikawa Y, Katoh H, Negishi M (2004) The Semaphorin 4D receptor Plexin-B1 is a GTPase-activating protein for R-Ras. Science 305:862–865
Yang T, Terman JR (2012) 14-3-3epsilon couples protein kinase A to semaphoring signaling and silences plexin Ras GAP-mediated axonal repulsion. Neuron 74:108–121
Bell CH, Aricescu AR, Jones EY, Siebold C (2011) A dual binding mode for RhoGTPases in plexin signalling. PLoS Biol 9:e1001134
Tong Y, Hota PK, Penachioni JY, Hamaneh MB, Kim S, Alviani RS, Shen L, He H, Tempel W, Tamagnone L, Park HW, Buck M (2009) Structure and function of the intracellular region of the plexin-b1 transmembrane receptor. J Biol Chem 284:35962–35972
Oinuma I, Katoh H, Negishi M (2004) Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 24:11473–11480
Perrot V, Vazquez-Prado J, Gutkind JS (2002) Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 277:43115–43120
Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M (2000) Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem 275:20020–20026
Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C (1999) M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem 274:23850–23857
Sakurai A, Gavard J, Annas-Linhares Y, Basile JR, Amornphimoltham P, Palmby TR, Yagi H, Zhang F, Randazzo PA, Li X, Weigert R, Gutkind JS (2010) Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras. Mol Cell Biol 30:3086–3098
Wang Y, He H, Srivastava N, Vikarunnessa S, Chen YB, Jiang J, Cowan CW, Zhang X (2012) Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal 5:ra6
Ito Y, Oinuma I, Katoh H, Kaibuchi K, Negishi M (2006) Sema4D/plexin-B1 activates GSK-3beta through R-Ras GAP activity, inducing growth cone collapse. EMBO Rep 7:704–709
Oinuma I, Katoh H, Negishi M (2006) Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating beta (1) integrin activity. J Cell Biol 173:601–613
Tomar A, Lim ST, Lim Y, Schlaepfer DD (2009) A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells. J Cell Sci 122:1852–1862
Richter M, Murai KK, Bourgin C, Pak DT, Pasquale EB (2007) The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci 27:14205–14215
Dai Y, Walker SA, de Vet E, Cook S, Welch HC, Lockyer PJ (2011) Ca2+-dependent monomer and dimer formation switches CAPRI Protein between Ras GTPase-activating protein (GAP) and RapGAP activities. J Biol Chem 286:19905–19916
Driessens MH, Hu H, Nobes CD, Self A, Jordens I, Goodman CS, Hall A (2001) Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr Biol 11:339–344
Driessens MH, Olivo C, Nagata K, Inagaki M, Collard JG (2002) B plexins activate Rho through PDZ-RhoGEF. FEBS Lett 529:168–172
Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL (2002) The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci USA 99:12085–12090
Swiercz JM, Kuner R, Behrens J, Offermanns S (2002) Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35:51–63
Shalaby MA, Hampson L, Oliver A, Hampson I (2011) Identification of PlexinD1 and AHDC1 as a putative interactors for Tip-1 protein. Genes & Genomics 33:399–405
Zhuang B, Su YS, Sockanathan S (2009) FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 61:359–372
Okada H, Uezu A, Mason FM, Soderblom EJ, Moseley MA 3rd, Soderling SH (2011) SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes. Sci Signal. 4:rs13
Barberis D, Casazza A, Sordella R, Corso S, Artigiani S, Settleman J, Comoglio PM, Tamagnone L (2005) p190 Rho-GTPase-activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci 118:4689–4700
Shimizu A, Mammoto A, Italiano JE Jr, Pravda E, Dudley AC, Ingber DE, Klagsbrun M (2008) ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells. J Biol Chem 283:27230–27238
Tatsis N, Lannigan DA, Macara IG (1998) The function of the p190 Rho GTPase-activating protein is controlled by its N-terminal GTP binding domain. J Biol Chem 273:34631–34638
Lévay M, Settleman J, Ligeti E (2009) Regulation of the substrate preference of p190RhoGAP by protein kinase C-mediated phosphorylation of a phospholipid binding site. Biochemistry 48:8615–8623
Mori K, Amano M, Takefuji M, Kato K, Morita Y, Nishioka T, Matsuura Y, Murohara T, Kaibuchi K (2009) Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. J Biol Chem 284:5067–5076
Bass MD, Morgan MR, Roach KA, Settleman J, Goryachev AB, Humphries MJ (2008) p190RhoGAP is the convergence point of adhesion signals from alpha 5 beta 1 integrin and syndecan-4. J Cell Biol 181:1013–1026
Bartolomé RA, Wright N, Molina-Ortiz I, Sánchez-Luque FJ, Teixidó J (2008) Activated G(alpha)13 impairs cell invasiveness through p190RhoGAP-mediated inhibition of RhoA activity. Cancer Res 68:8221–8230
Shen CH, Chen HY, Lin MS, Li FY, Chang CC, Kuo ML, Settleman J, Chen RH (2008) Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Cancer Res 68:7779–7787
Mammoto A, Huang S, Ingber DE (2007) Filamin links cell shape and cytoskeletal structure to Rho regulation by controlling accumulation of p190RhoGAP in lipid rafts. J Cell Sci 120:456–467
Oinuma I, Kawada K, Tsukagoshi K, Negishi M(2012) Rnd1 and Rnd3 targeting to lipid raft is required for p190 RhoGAP activation. Mol Biol Cell 23:1593–1604
Bradley WD, Hernández SE, Settleman J, Koleske AJ (2006) Integrin signaling through Arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane. Mol Biol Cell 17:4827–4836
Roney KE, O’Connor BP, Wen H, Holl EK, Guthrie EH, Davis BK, Jones SW, Jha S, Sharek L, Garcia-Mata R, Bear JE, Ting JP (2011) Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation. PLoS ONE 6:e24795
McClelland L, Chen Y, Soong J, Kuo I, Scott G (2011) Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma. Pigment Cell Melanoma Res 24:165–174
Sakurai A, Jian X, Lee CJ, Manavski Y, Chavakis E, Donaldson J, Randazzo PA, Gutkind JS (2011) Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein. J Biol Chem 286:34335–34345
Parachoniak CA, Luo Y, Abella JV, Keen JH, Park M (2011) GGA3 functions as a switch to promote Met receptor recycling, essential for sustained ERK and cell migration. Dev Cell 20:751–763
Basile JR, Afkhami T, Gutkind JS (2005) Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 16:6889–6898
Fan S, Meng Q, Laterra JJ, Rosen EM (2009) Role of Src signal transduction pathways in scatter factor-mediated cellular protection. J Biol Chem 284:7561–7577
Segarra J, Balenci L, Drenth T, Maina F, Lamballe F (2006) Combined signaling through ERK, PI3 K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration. J Biol Chem 281:4771–4778
Wannemacher KM, Zhu L, Jiang H, Fong KP, Stalker TJ, Lee D, Tran AN, Neeves KB, Maloney S, Kumanogoh A, Kikutani H, Hammer DA, Diamond SL, Brass LF (2010) Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D. Blood 116:5707–5715
Jiang SX, Whitehead S, Aylsworth A, Slinn J, Zurakowski B, Chan K, Li J, Hou ST (2010) Neuropilin 1 directly interacts with Fer kinase to mediate semaphorin 3A-induced death of cortical neurons. J Biol Chem 285:9908–9918
Shapovalova Z, Tabunshchyk K, Greer PA (2007) The Fer tyrosine kinase regulates an axon retraction response to Semaphorin 3A in dorsal root ganglion neurons. BMC Dev Biol 7:133
Mitsui N, Inatome R, Takahashi S, Goshima Y, Yamamura H, Yanagi S (2002) Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling. EMBO J 21:3274–3285
Deo RC, Schmidt EF, Elhabazi A, Togashi H, Burley SK, Strittmatter SM (2004) Structural bases for CRMP function in plexin-dependent semaphorin3A signaling. EMBO J 23:9–22
Buel GR, Rush J, Ballif BA (2010) Fyn promotes phosphorylation of collapsin response mediator protein 1 at tyrosine 504, a novel, isoform-specific regulatory site. J Cell Biochem 111:20–28
Sasaki Y, Cheng C, Uchida Y, Nakajima O, Ohshima T, Yagi T, Taniguchi M, Nakayama T, Kishida R, Kudo Y, Ohno S, Nakamura F, Goshima Y (2002) Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35:907–920
Lin X, Ogiya M, Takahara M, Yamaguchi W, Furuyama T, Tanaka H, Tohyama M, Inagaki S (2007) Sema4D-plexin-B1 implicated in regulation of dendritic spine density through RhoA/ROCK pathway. Neurosci Lett 428:1–6
Tripathi BK, Zelenka PS (2009) Cdk5-dependent regulation of Rho activity, cytoskeletal contraction, and epithelial cell migration via suppression of Src and p190RhoGAP. Mol Cell Biol 29:6488–6499
Ahmed A, Eickholt BJ (2007) Intracellular kinases in semaphorin signaling. Adv Exp Med Biol 600:24–37
Aurandt J, Li W, Guan KL (2006) Semaphorin 4D activates the MAPK pathway downstream of plexin-B1. Biochem J 394:459–464
Yang YH, Zhou H, Binmadi NO, Proia P, Basile JR (2011) Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells. PLoS ONE 6:e25826
Lin PC, Chan PM, Hall C, Manser E (2011) Collapsin response mediator proteins (CRMPs) are a new class of microtubule-associated protein (MAP) that selectively interacts with assembled microtubules via a taxol-sensitive binding interaction. J Biol Chem 286:41466–41478
Shelly M, Cancedda L, Lim BK, Popescu AT, Cheng PL, Gao H, Poo MM (2011) Semaphorin3A regulates neuronal polarization by suppressing axon formation and promoting dendrite growth. Neuron 71:433–446
Pulina MV, Rizzuto R, Brini M, Carafoli E (2006) Inhibitory interaction of the plasma membrane Na+/Ca2+ exchangers with the 14-3-3 proteins. J Biol Chem 281:19645–19654
Barberis D, Artigiani S, Casazza A, Corso S, Giordano S, Love CA, Jones EY, Comoglio PM, Tamagnone L (2004) Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility. FASEB J 18:592–594
Oinuma I, Ito Y, Katoh H, Negishi M (2010) Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons. J Biol Chem 285:28200–28209
Chadborn NH, Ahmed AI, Holt MR, Prinjha R, Dunn GA, Jones GE, Eickholt BJ (2006) PTEN couples Sema3A signalling to growth cone collapse. J Cell Sci 119:951–957
Eickholt BJ, Walsh FS, Doherty P (2002) An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J Cell Biol 157:211–217
Yucel G, Oro AE (2011) Cell migration: GSK3β steers the cytoskeleton’s tip. Cell 144:319–321
Terman JR, Kolodkin AL (2004) Nervy links protein kinase a to plexin-mediated semaphorin repulsion. Science 303:1204–1207
Fiedler SE, Schillace RV, Daniels CJ, Andrews SF, Carr DW (2010) Myeloid translocation gene 16b is a dual A-kinase anchoring protein that interacts selectively with plexins in a phospho-regulated manner. FEBS Lett 584:873–877
Togashi H, Schmidt EF, Strittmatter SM (2006) RanBPM contributes to Semaphorin3A signaling through plexin-A receptors. J Neurosci 26:4961–4969
Laht P, Pill K, Haller E, Veske A. Plexin-B3 interacts with EB-family proteins through a conserved motif. Biochim Biophys Acta. 2012 Feb 21
Cheng L, Lemmon S, Lemmon V (2005) RanBPM is an L1-interacting protein that regulates L1-mediated mitogen-activated protein kinase activation. J Neurochem 94:1102–1110
Hung RJ, Yazdani U, Yoon J, Wu H, Yang T, Gupta N, Huang Z, van Berkel WJ, Terman JR (2010) Mical links semaphorins to F-actin disassembly. Nature 463:823–827
Terman JR, Mao T, Pasterkamp RJ, Yu HH, Kolodkin AL (2002) MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109:887–900
Hung RJ, Terman JR (2011) Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL-mediated actin filament disassembly. Cytoskeleton (Hoboken) 68:415–433
Schmidt EF, Shim SO, Strittmatter SM (2008) Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein. J Neurosci 28:2287–2297
Nadella M, Bianchet MA, Gabelli SB, Barrila J, Amzel LM (2005) Structure and activity of the axon guidance protein MICAL. Proc Natl Acad Sci USA 102:16830–16835
Hung RJ, Pak CW, Terman JR (2011) Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334:1710–1713
Siebold C, Berrow N, Walter TS, Harlos K, Owens RJ, Stuart DI, Terman JR, Kolodkin AL, Pasterkamp RJ, Jones EY (2005) High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule. Proc Natl Acad Sci USA 102:16836–16841
Bork P, Doerks T, Springer TA, Snel B (1999) Domains in plexins: links to integrins and transcription factors. Trends Biochem Sci 24:261–263
Gherardi E, Love CA, Esnouf RM, Jones EY (2004) The sema domain. Curr Opin Struct Biol 14:669–678
Antipenko A, Himanen JP, van Leyen K, Nardi-Dei V, Lesniak J, Barton WA, Rajashankar KR, Lu M, Hoemme C, Püschel AW, Nikolov DB (2003) Structure of the semaphorin-3A receptor binding module. Neuron 39:589–598
Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY, Esnouf RM (2003) The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol 10:843–848
Nogi T, Yasui N, Mihara E, Matsunaga Y, Noda M, Yamashita N, Toyofuku T, Uchiyama S, Goshima Y, Kumanogoh A, Takagi J (2010) Structural basis for semaphorin signalling through the plexin receptor. Nature 467:1123–1127
Janssen BJ, Robinson RA, Pérez-Brangulí F, Bell CH, Mitchell KJ, Siebold C, Jones EY (2010) Structural basis of semaphorin-plexin signalling. Nature 467:1118–1122
Liu H, Juo ZS, Shim AH, Focia PJ, Chen X, Garcia KC, He X (2010) Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1. Cell 142:749–761
Niemann HH (2011) Structural insights into Met receptor activation. Eur J Cell Biol 90:972–981
Stamos J, Lazarus RA, Yao X, Kirchhofer D, Wiesmann C (2004) Crystal structure of the HGF beta-chain in complex with the Sema domain of the Met receptor. EMBO J 23:2325–2335
Luo BH, Springer TA (2006) Integrin structures and conformational signaling. Curr Opin Cell Biol 18:579–586
Takahashi T, Strittmatter SM (2001) Plexin-A1 autoinhibition by the plexin sema domain. Neuron 29:429–439
Kozlov G, Perreault A, Schrag JD, Park M, Cygler M, Gehring K, Ekiel I (2004) Insights into function of PSI domains from structure of the Met receptor PSI domain. Biochem Biophys Res Commun 321:234–240
Xiong JP, Stehle T, Goodman SL, Arnaout MA (2004) A novel adaptation of the integrin PSI domain revealed from its crystal structure. J Biol Chem 279:40252–40254
Shi M, Sundramurthy K, Liu B, Tan SM, Law SK, Lescar J (2005) The crystal structure of the plexin-semaphorin-integrin domain/hybrid domain/I-EGF1 segment from the human integrin beta2 subunit at 1.8-A resolution. J Biol Chem 280:30586–30593
Mould AP, Travis MA, Barton SJ, Hamilton JA, Askari JA, Craig SE, Macdonald PR, Kammerer RA, Buckley PA, Humphries MJ (2005) Evidence that monoclonal antibodies directed against the integrin beta subunit plexin/semaphorin/integrin domain stimulate function by inducing receptor extension. J Biol Chem 280:4238–4246
Xiao T, Takagi J, Coller BS, Wang JH, Springer TA (2004) Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 432:59–67
Daburon V, Mella S, Plouhinec JL, Mazan S, Crozatier M, Vincent A (2008) The metazoan history of the COE transcription factors. Selection of a variant HLH motif by mandatory inclusion of a duplicated exon in vertebrates. BMC Evol Biol 8:131
Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnik-Schöneborn S, Mrug M, Sweeney W, Avner ED, Zerres K, Guay-Woodford LM, Somlo S, Germino GG (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 70:1305–1317
Ma Q, Zhang K, Guin S, Zhou YQ, Wang MH (2010) Deletion or insertion in the first immunoglobulin-plexin-transcription (IPT) domain differentially regulates expression and tumorigenic activities of RON receptor Tyrosine Kinase. Mol Cancer 9:307
Zhou YQ, He C, Chen YQ, Wang D, Wang MH (2003) Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential. Oncogene 22:186–197
Zhang K, Zhou YQ, Yao HP, Wang MH (2010) Alterations in a defined extracellular region of the RON receptor tyrosine kinase promote RON-mediated motile and invasive phenotypes in epithelial cells. Int J Oncol 36:255–264
Russ WP, Engelman DM (2000) The GxxxG motif: a framework for transmembrane helix–helix association. J Mol Biol 296:911–919
de Wit J, Verhaagen J (2007) Proteoglycans as modulators of axon guidance cue function. Adv Exp Med Biol 600:73–89
Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975
Bondeva T, Wojciech S, Wolf G (2011) Advanced glycation end products inhibit adhesion ability of differentiated podocytes in a neuropilin-1-dependent manner. Am J Physiol Renal Physiol 301:F852–F870
Esselens C, Malapeira J, Colomé N, Casal C, Rodríguez-Manzaneque JC, Canals F, Arribas J (2010) The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem 285:2463–2473
Artigiani S, Barberis D, Fazzari P, Longati P, Angelini P, van de Loo JW, Comoglio PM, Tamagnone L (2003) Functional regulation of semaphorin receptors by proprotein convertases. J Biol Chem 278:10094–10101
Aricescu AR, Jones EY (2007) Immunoglobulin superfamily cell adhesion molecules: zippers and signals. Curr Opin Cell Biol 19:543–550
Tong Y, Buck M (2005) 1H, 15 N and 13C Resonance assignments and secondary structure determination reveal that the minimal Rac1 GTPase binding domain of plexin-B1 has a ubiquitin fold. J Biomol NMR 31:369–370
Tong Y, Hughes D, Placanica L, Buck M (2005) When monomers are preferred: a strategy for the identification and disruption of weakly oligomerized proteins. Structure 13:7–15
Kiel C, Wohlgemuth S, Rousseau F, Schymkowitz J, Ferkinghoff-Borg J, Wittinghofer F, Serrano L (2005) Recognizing and defining true Ras binding domains II: in silico prediction based on homology modelling and energy calculations. J Mol Biol 348:759–775
Bouguet-Bonnet S, Buck M (2008) Compensatory and long-range changes in picosecond-nanosecond main-chain dynamics upon complex formation: 15 N relaxation analysis of the free and bound states of the ubiquitin-like domain of human plexin-B1 and the small GTPase Rac1. J Mol Biol 377:1474–1487
Zhang L, Bouguet-Bonnet S, Buck M (2011) “Combining NMR and Molecular Dynamics Studies for Insights into the Allostery of Small GTPase-Protein Interactions”—book chapter for Methods in Molecular Biology: Allostery.Methods Proto (Humana Press) 796:235-56
He H, Yang T, Terman JR, Zhang X (2009) Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. Proc Natl Acad Sci USA 106:15610–15615
Kim, S, Hota, PK, Zhang, L, Borthakur, Buck, M (2012) in advanced preparation
Unpublished—solution structure pdb id 2OS6
Ward CW, Lawrence MC, Streltsov VA, Adams TE, McKern NM (2007) The insulin and EGF receptor structures: new insights into ligand-induced receptor activation. Trends Biochem Sci 32:129–137
Vinogradova O, Velyvis A, Velyviene A, Hu B, Haas T, Plow E, Qin JA (2002) Structural mechanism of integrin alpha(IIb)beta(3) “inside-out” activation as regulated by its cytoplasmic face. Cell 110:587–597
Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Müller S, Knapp S (2009) Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 136:352–363
Dent EW, Gertler FB (2003) Cytoskeletal dynamics and transport in growth cone motility and axon guidance. Neuron 40:209–227
Marinissen MJ, Gutkind JS (2005) Scaffold proteins dictate Rho GTPase-signaling specificity. Trends Biochem Sci 30:423–426
Murai T, Maruyama Y, Mio K, Nishiyama H, Suga M, Sato C (2011) Low cholesterol triggers membrane microdomain-dependent CD44 shedding and suppresses tumor cell migration. J Biol Chem 286:1999–2007
Haklai-Topper L, Mlechkovich G, Savariego D, Gokhman I, Yaron A (2010) Cis interaction between Semaphorin6A and Plexin-A4 modulates the repulsive response to Sema6A. EMBO J 29:2635–2645
Bashaw GJ, Klein R (2010) Signaling from axon guidance receptors. Cold Spring Harb Perspect Biol. 2:a001941
Parkhurst CN, Zampieri N, Chao MV (2010) Nuclear localization of the p75 neurotrophin receptor intracellular domain. J Biol Chem 285:5361–5368
Mann F, Rougon G (2007) Mechanisms of axon guidance: membrane dynamics and axonal transport in semaphorin signalling. J Neurochem 102:316–323
Zylbersztejn K, Petkovic M, Burgo A, Deck M, Garel S, Marcos S, Bloch-Gallego E, Nothias F, Serini G, Bagnard D, Binz T, Galli T (2012) The vesicular SNARE Synaptobrevin is required for Semaphorin 3A axonal repulsion. J Cell Biol 196:37–46
Casaletto JB, McClatchey AI (2012) Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer 12(6):387–400
Nakai Y, Kamiguchi H (2002) Migration of nerve growth cones requires detergent-resistant membranes in a spatially defined and substrate-dependent manner. J Cell Biol 159:1097–1108
Moretti S, Procopio A, Lazzarini R, Rippo MR, Testa R, Marra M, Tamagnone L, Catalano A (2008) Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts. Blood 111:2290–2299
Lu YC, Chen HC (2011) Involvement of lipid rafts in adhesion-induced activation of Met and EGFR. J Biomed Sci 18:78
Ellis S, Mellor H (2000) Regulation of endocytic traffic by rho family GTPases. Trends Cell Biol 10:85–88
Jurney WM, Gallo G, Letourneau PC, McLoon SC (2002) Rac1-mediated endocytosis during ephrin-A2- and semaphorin 3A-induced growth cone collapse. J Neurosci 22:6019–6028
Salikhova A, Wang L, Lanahan AA, Liu M, Simons M, Leenders WP, Mukhopadhyay D, Horowitz A (2008) Vascular endothelial growth factor and semaphorin induce neuropilin-1 endocytosis via separate pathways. Circ Res 103:e71–e79
Gomes DA, Rodrigues MA, Leite MF, Gomez MV, Varnai P, Balla T, Bennett AM, Nathanson MH (2008) c-Met must translocate to the nucleus to initiate calcium signals. J Biol Chem 283:4344–4351
Li N, Lorinczi M, Ireton K, Elferink LA (2007) Specific Grb2-mediated interactions regulate clathrin-dependent endocytosis of the cMet-tyrosine kinase. J Biol Chem 282:16764–16775
Carter S, Urbé S, Clague MJ (2004) The met receptor degradation pathway: requirement for Lys48-linked polyubiquitin independent of proteasome activity. J Biol Chem 279:52835–52839
Sabo SL, McAllister AK (2003) Mobility and cycling of synaptic protein-containing vesicles in axonal growth cone filopodia. Nat Neurosci 6:1264–1269
Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, Miyawaki A, Kamiguchi H (2007) Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone. Nat Neurosci 10:58–66
Sutton MA, Schuman EM (2006) Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127:49–58
Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR (2005) Local translation of RhoA regulates growth cone collapse. Nature 436:1020–1024
Tcherkezian J, Brittis PA, Thomas F, Roux PP, Flanagan JG (2010) Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141:632–644
Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179
Mitin N, Rossman KL, Der CJ (2005) Signaling interplay in Ras superfamily function. Curr Biol 15:R563–R574
Govek EE, Hatten ME, Van Aelst L (2011) The role of Rho GTPase proteins in CNS neuronal migration. Dev Neurobiol. 71:528–553
Shang X, Cancelas JA, Li L, Guo F, Liu W, Johnson JF, Ficker A, Daria D, Geiger H, Ratner N, Zheng Y (2011) R-Ras and Rac GTPase Cross-talk Regulates Hematopoietic Progenitor Cell Migration, Homing, and Mobilization. J Biol Chem 286:24068–24078
Goryachev AB, Pokhilko AV (2006) Computational model explains high activity and rapid cycling of Rho GTPases within protein complexes. PLoS Comput Biol 2:e172
Lipshtat A, Jayaraman G, He JC, Iyengar R (2010) Design of versatile biochemical switches that respond to amplitude, duration, and spatial cues. Proc. Natl. Acad. Sci. U. S. A. 107:1247–1252
Tsyganov MA, Kolch W, Kholodenko BN (2012) The topology design principles that determine the spatiotemporal dynamics of G-protein cascades. Mol BioSyst 8:730–743
Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E (1999) An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci U S A. 96:13813–13818
Vayssière B, Zalcman G, Mahé Y, Mirey G, Ligensa T, Weidner KM, Chardin P, Camonis J (2000) Interaction of the Grb7 adapter protein with Rnd1, a new member of the Rho family. FEBS Lett 467:91–96
Bunney TD, Opaleye O, Roe SM, Vatter P, Baxendale RW, Walliser C, Everett KL, Josephs MB, Christow C, Rodrigues-Lima F, Gierschik P, Pearl LH, Katan M (2009) Structural insights into formation of an active signaling complex between Rac and phospholipase C gamma 2. Mol Cell 34:223–233
Binmadi NO, Proia P, Zhou H, Yang YH, Basile JR (2011) Rho-mediated activation of PI(4)P5 K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D. Angiogenesis 14:309–319
Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657
Czech MP (2000) PIP2 and PIP3: complex roles at the cell surface. Cell 100:603–606
Glinka Y, Stoilova S, Mohammed N, Prud’homme GJ (2011) Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis 32:613–621
Kang HR, Lee CG, Homer RJ, Elias JA (2007) Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis. J Exp Med 204:1083–1093
Kamata H, Hirata H (1999) Redox regulation of cellular signalling. Cell Signal 11:1–14
Rhee SG (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science 312:1882–1883
Fischer OM, Giordano S, Comoglio PM, Ullrich A (2004) Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J Biol Chem 279:28970–28978
Ferraro D, Corso S, Fasano E, Panieri E, Santangelo R, Borrello S, Giordano S, Pani G, Galeotti T (2006) Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene 25:3689–3698
Lu Y, Xiong Y, Huo Y, Han J, Yang X, Zhang R, Zhu DS, Klein-Hessling S, Li J, Zhang X, Han X, Li Y, Shen B, He Y, Shibuya M, Feng GS, Luo J (2011) Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway. Proc Natl Acad Sci USA 108:2957–2962
Monaghan-Benson E, Burridge K (2009) The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species. J Biol Chem 284:25602–25611
Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264:85–97
Nimnual AS, Taylor LJ, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5:236–241
Sun Q, Zhou H, Binmadi NO, Basile JR (2009) Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J Biol Chem 284:32066–32074
Coma S, Shimizu A, Klagsbrun M (2011) Hypoxia induces tumor and endothelial cell migration in a Semaphorin 3F- and VEGF-dependent manner via transcriptional repression of their common receptor Neuropilin 2. Cell Adh Migr. 5:266–275
Bae D, Lu S, Taglienti CA, Mercurio AM (2008) Metabolic stress induces the lysosomal degradation of neuropilin-1 but not neuropilin-2. J Biol Chem 283:28074–28080
Morinaka A, Yamada M, Itofusa R, Funato Y, Yoshimura Y, Nakamura F, Yoshimura T, Kaibuchi K, Goshima Y, Hoshino M, Kamiguchi H, Miki H. (2011) Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse. Sci Signal. 4:ra26
Heo J, Campbell SL (2006) Ras regulation by reactive oxygen and nitrogen species. Biochemistry 45:2200–2210
Heo J, Raines KW, Mocanu V, Campbell SL (2006) Redox regulation of RhoA. Biochemistry 45:14481–14489
Day AM, Veal EA (2010) Hydrogen peroxide-sensitive cysteines in the Sty1 MAPK regulate the transcriptional response to oxidative stress. J Biol Chem 285:7505–7516
Barford D (2004) The role of cysteine residues as redox-sensitive regulatory switches. Curr Opin Struct Biol 14:679–686
Gatherwright, Hota PK, and Buck M. unpublished data
Clapham DE (2007) Calcium signaling. Cell 131:1047–1058
Gomez TM, Spitzer NC (2000) Regulation of growth cone behavior by calcium: new dynamics to earlier perspectives. J Neurobiol 44:174–183
Yoshida T, Uchida S, Mishina M (2009) Regulation of synaptic vesicle accumulation and axon terminal remodeling during synapse formation by distinct Ca signaling. J Neurochem 111:160–170
Gomez TM, Zheng JQ (2006) The molecular basis for calcium-dependent axon pathfinding. Nat Rev Neurosci 7:115–125
Henley J, Poo MM (2004) Guiding neuronal growth cones using Ca2 + signals. Trends Cell Biol 14:320–330
Nishiyama M, Togashi K, von Schimmelmann MJ, Lim CS, Maeda S, Yamashita N, Goshima Y, Ishii S, Hong K (2011) Semaphorin 3A induces Ca(V)2.3 channel-dependent conversion of axons to dendrites. Nat Cell Biol 13:677–686
Cullen PJ, Lockyer PJ (2002) Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol 3:339–348
Ying Z, Giachini FR, Tostes RC, Webb RC (2009) PYK2/PDZ-RhoGEF links Ca2 + signaling to RhoA. Arterioscler Thromb Vasc Biol 29:1657–1663
Derewenda U, Oleksy A, Stevenson AS, Korczynska J, Dauter Z, Somlyo AP, Otlewski J, Somlyo AV, Derewenda ZS (2004) The crystal structure of RhoA in complex with the DH/PH fragment of PDZRhoGEF, an activator of the Ca(2 +) sensitization pathway in smooth muscle. Structure 12:1955–1965
Song HJ, Ming GL, Poo MM (1997) cAMP-induced switching in turning direction of nerve growth cones. Nature 388:275–279
Togashi K, von Schimmelmann MJ, Nishiyama M, Lim CS, Yoshida N, Yun B, Molday RS, Goshima Y, Hong K (2008) Cyclic GMP-gated CNG channels function in Sema3A-induced growth cone repulsion. Neuron 58:694–707
Nishiyama M, von Schimmelmann MJ, Togashi K, Findley WM, Hong K (2008) Membrane potential shifts caused by diffusible guidance signals direct growth-cone turning. Nat Neurosci 11:762–771
Behar O, Mizuno K, Badminton M, Woolf CJ (1999) Semaphorin 3A growth cone collapse requires a sequence homologous to tarantula hanatoxin. Proc Natl Acad Sci U S A. 96:13501–13505
Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M (1998) Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281:1515–1518
Acknowledgments
We apologize to investigators whose important work we omitted to cite due to space restraints and want to thank several colleagues and many members of the plexin/sema/neuropilin community. We are especially grateful to John Basile, Alain Chedotal, Jonathan Duke-Cohen, Silvio Gutkind, Michael Klagsbrun, Alex Kolodkin, Fanny Mann, Hee-Won Park, Andreas Püschel, Jakub Swiercz, Junichi Takagi, Luca Tamagnone, Jonathan Terman, Yufeng Tong and Thomas Worzfeld for their comments on parts of this review, as well as to an anonymous reviewer and several members of the Buck lab., particularly Susmita Borthakur and SoonJeung Kim for their help. Taeku Kim assisted with references. This project is supported by NIH Grant GM073071.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hota, P.K., Buck, M. Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell. Mol. Life Sci. 69, 3765–3805 (2012). https://doi.org/10.1007/s00018-012-1019-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-012-1019-0