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LIM kinases: function, regulation and association with human disease

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Abstract

The LIM kinase family consists of just two members: LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2). With uniquely organised signalling domains, LIM kinases are regulated by several upstream signalling pathways, principally acting downstream of Rho GTPases to influence the architecture of the actin cytoskeleton by regulating the activity of the cofilin family proteins cofilin1, cofilin2 and destrin. Although the LIM kinases are very homologous, particularly when comparing kinase domains, there is emerging evidence that each may be subject to different regulatory pathways and may contribute to both distinct and overlapping cellular and developmental functions. Normal central nervous system development is reliant upon the presence of LIMK1, and its deletion has been implicated in the development of the human genetic disorder Williams syndrome. Normal testis development, on the other hand, is disrupted by the deletion of LIMK2. In addition, the possible involvement of each kinase in cardiovascular disorders as well as cancer has recently emerged. The LIM kinases have been proposed to play an important role in tumour-cell invasion and metastasis; fine-tuning the balance between phosphorylated and non-phosphorylated cofilin may be a significant determinant of tumour-cell metastatic potential. In this review, we outline the structure, regulation and function of LIM kinases and their functions at cellular and organismal levels, as well as their possible contributions to human disease.

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References

  1. Mizuno K, Okano I, Ohashi K, Nunoue K, Kuma K, Miyata T, Nakamura T (1994) Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. Oncogene 9:1605–1612

    PubMed  CAS  Google Scholar 

  2. Nunoue K, Ohashi K, Okano I, Mizuno K (1995) LIMK-1 and LIMK-2, two members of a LIM motif-containing protein kinase family. Oncogene 11:701–710

    PubMed  CAS  Google Scholar 

  3. Okano I, Hiraoka J, Otera H, Nunoue K, Ohashi K, Iwashita S, Hirai M, Mizuno K (1995) Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs. J Biol Chem 270:31321–31330

    PubMed  CAS  Google Scholar 

  4. Bernard O, Ganiatsas S, Kannourakis G, Dringen R (1994) Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ 5:1159–1171

    PubMed  CAS  Google Scholar 

  5. Koshimizu U, Takahashi H, Yoshida MC, Nakamura T (1997) cDNA cloning, genomic organization, and chromosomal localization of the mouse LIM motif-containing kinase gene, LIMK2. Biochem Biophys Res Commun 241:243–250

    PubMed  CAS  Google Scholar 

  6. Takahashi T, Aoki S, Nakamura T, Koshimizu U, Matsumoto K, Nakamura T (1997) Xenopus LIM motif-containing protein kinase, XLIMk1, is expressed in the developing head structure of the embryo. Dev Dyn 209:196–205

    PubMed  CAS  Google Scholar 

  7. Ohashi K, Hosoya T, Takahashi K, Hing H, Mizuno K (2000) A Drosophila homolog of LIM-kinase phosphorylates cofilin and induces actin cytoskeletal reorganization. Molec Cell Biol Res Commun 276:1178–1185

    CAS  Google Scholar 

  8. Vartiainen MK, Mustonen T, Mattila PK, Ojala PJ, Thesleff I, Partanen J, Lappalainen P (2002) The three mouse actin-depolymerizing factor/cofilins evolved to fulfill cell-type-specific requirements for actin dynamics. Mol Biol Cell 13:183–194

    PubMed  CAS  Google Scholar 

  9. Yang EJ, Yoon JH, Min do S, Chung KC (2004) LIM kinase 1 activates cAMP-responsive element-binding protein during the neuronal differentiation of immortalized hippocampal progenitor cells. J Biol Chem 279:8903–8910

    PubMed  CAS  Google Scholar 

  10. Sacchetti P, Carpentier R, Segard P, Olive-Cren C, Lefebvre P (2006) Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1. Nucleic Acids Res 34:5515–5527

    PubMed  CAS  Google Scholar 

  11. Roovers K, Klein EA, Castagnino P, Assoian RK (2003) Nuclear translocation of LIM kinase mediates Rho–Rho kinase regulation of cyclin D1 expression. Dev Cell 5:273–284

    PubMed  CAS  Google Scholar 

  12. Bamburg JR (1999) Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu Rev Cell Dev Biol 15:185–230

    PubMed  CAS  Google Scholar 

  13. Ghosh M, Song X, Mouneimne G, Sidani M, Lawrence DS, Condeelis JS (2004) Cofilin promotes actin polymerization and defines the direction of cell motility. Science 304:743–746

    PubMed  CAS  Google Scholar 

  14. Lorenz M, DesMarais V, Macaluso F, Singer RH, Condeelis J (2004) Measurement of barbed ends, actin polymerization, and motility in live carcinoma cells after growth factor stimulation. Cell Motil Cytoskeleton 57:207–217

    PubMed  CAS  Google Scholar 

  15. Sumi T, Matsumoto K, Takai Y, Nakamura T (1999) Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2. J Cell Biol 147:1519–1532

    PubMed  CAS  Google Scholar 

  16. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895–898

    PubMed  CAS  Google Scholar 

  17. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K (2000) Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem 275:3577–3582

    PubMed  CAS  Google Scholar 

  18. Amano T, Tanabe K, Eto T, Narumiya S, Mizuno K (2001) LIM-kinase 2 induces formation of stress fibres, focal adhesions and membrane blebs, dependent on its activation by Rho-associated kinase-catalysed phosphorylation at threonine-505. Biochem J 354:149–159

    PubMed  CAS  Google Scholar 

  19. Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, Caroni P (1998) Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393:805–809

    PubMed  CAS  Google Scholar 

  20. Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, Nishida E, Mizuno K (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393:809–812

    PubMed  CAS  Google Scholar 

  21. Takahashi T, Koshimizu U, Abe H, Obinata T, Nakamura T (2001) Functional involvement of Xenopus LIM kinases in progression of oocyte maturation. Dev Biol 229:554–567

    PubMed  CAS  Google Scholar 

  22. Toshima J, Toshima JY, Amano T, Yang N, Narumiya S, Mizuno K (2001) Cofilin phosphorylation by protein kinase testicular protein kinase 1 and its role in integrin-mediated actin reorganization and focal adhesion formation. Mol Biol Cell 12:1131–1145

    PubMed  CAS  Google Scholar 

  23. Toshima J, Toshima JY, Takeuchi K, Mori R, Mizuno K (2001) Cofilin phosphorylation and actin reorganization activities of testicular protein kinase 2 and its predominant expression in testicular Sertoli cells. J Biol Chem 276:31449–31458

    PubMed  CAS  Google Scholar 

  24. Nakano K, Kanai-Azuma M, Kanai Y, Moriyama K, Yazaki K, Hayashi Y, Kitamura N (2003) Cofilin phosphorylation and actin polymerization by NRK/NESK, a member of the germinal center kinase family. Exp Cell Res 287:219–227

    PubMed  CAS  Google Scholar 

  25. Davila M, Frost AR, Grizzle WE, Chakrabarti R (2003) LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer. J Biol Chem 278:36868–36875

    PubMed  CAS  Google Scholar 

  26. Yoshioka K, Foletta V, Bernard O, Itoh K (2003) A role for LIM kinase in cancer invasion. Proc Natl Acad Sci USA 100:7247–7252

    PubMed  CAS  Google Scholar 

  27. Suyama E, Wadhwa R, Kawasaki H, Yaguchi T, Kaul SC, Nakajima M, Taira K (2004) LIM kinase-2 targeting as a possible anti-metastasis therapy. J Gene Med 6:357–363

    PubMed  CAS  Google Scholar 

  28. Hoogenraad CC, Akhmanova A, Galjart N, De Zeeuw CI (2004) LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome. Bioessays 26:141–150

    PubMed  CAS  Google Scholar 

  29. Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162:1089–1098

    PubMed  CAS  Google Scholar 

  30. Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY, Kimm K, Inoue I (2006) A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum Mol Genet 15:1722–1734

    PubMed  CAS  Google Scholar 

  31. Nagata K, Ohashi K, Yang N, Mizuno K (1999) The N-terminal LIM domain negatively regulates the kinase activity of LIM-kinase 1. Biochem J 343 Pt 1:99–105

    PubMed  CAS  Google Scholar 

  32. Tomiyoshi G, Horita Y, Nishita M, Ohashi K, Mizuno K (2004) Caspase-mediated cleavage and activation of LIM-kinase 1 and its role in apoptotic membrane blebbing. Genes Cells 9:591–600

    PubMed  CAS  Google Scholar 

  33. Hiraoka J, Okano I, Higuchi O, Yang N, Mizuno K (1996) Self-association of LIM-kinase 1 mediated by the interaction between an N-terminal LIM domain and a C-terminal kinase domain. FEBS Lett 399:117–121

    PubMed  CAS  Google Scholar 

  34. Nishiya N, Sabe H, Nose K, Shibanuma M (1998) The LIM domains of hic-5 protein recognize specific DNA fragments in a zinc-dependent manner in vitro. Nucleic Acids Res 26:4267–4273

    PubMed  CAS  Google Scholar 

  35. Yang N, Higuchi O, Mizuno K (1998) Cytoplasmic localization of LIM-kinase 1 is directed by a short sequence within the PDZ domain. Exp Cell Res 241:242–252

    PubMed  CAS  Google Scholar 

  36. Yang N, Mizuno K (1999) Nuclear export of LIM-kinase 1, mediated by two leucine-rich nuclear-export signals within the PDZ domain. Biochem J 338(Pt 3):793–798

    PubMed  CAS  Google Scholar 

  37. Goyal P, Pandey D, Siess W (2006) Phosphorylation-dependent regulation of unique nuclear and nucleolar localization signals of LIM-kinase 2 in endothelial cells. J Biol Chem 281:25223–25230

    PubMed  CAS  Google Scholar 

  38. Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52

    PubMed  CAS  Google Scholar 

  39. Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) LIMK1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271–1281

    PubMed  CAS  Google Scholar 

  40. Sumi T, Matsumoto K, Nakamura T (2001) Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. J Biol Chem 276:670–676

    PubMed  CAS  Google Scholar 

  41. Edwards DC, Sanders LC, Bokoch GM, Gill GN (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1:253–259

    PubMed  CAS  Google Scholar 

  42. Dan C, Kelly A, Bernard O, Minden A (2001) Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. J Biol Chem 276:32115–32121

    PubMed  CAS  Google Scholar 

  43. Sumi T, Matsumoto K, Shibuya A, Nakamura T (2001) Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. J Biol Chem 276:23092–23096

    PubMed  CAS  Google Scholar 

  44. Misra UK, Deedwania R, Pizzo SV (2005) Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem 280:26278–26286

    PubMed  CAS  Google Scholar 

  45. Wu H, Zheng Y, Wang ZX (2003) Evaluation of the catalytic mechanism of the p21-activated protein kinase PAK2. Biochemistry 42:1129–1139

    PubMed  CAS  Google Scholar 

  46. Li R, Soosairajah J, Harari D, Citri A, Price J, Ng HL, Morton CJ, Parker MW, Yarden Y, Bernard O (2006) Hsp90 increases LIM kinase activity by promoting its homo-dimerization. FASEB J 20:1218–1220

    PubMed  CAS  Google Scholar 

  47. Edwards DC, Gill GN (1999) Structural features of LIM kinase that control effects on the actin cytoskeleton. J Biol Chem 274:11352–11361

    PubMed  CAS  Google Scholar 

  48. Kobayashi M, Nishita M, Mishima T, Ohashi K, Mizuno K (2006) MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. EMBO J 25:713–726

    PubMed  CAS  Google Scholar 

  49. Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O (2005) Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J 24:473–486

    PubMed  CAS  Google Scholar 

  50. Niwa R, Nagata-Ohashi K, Takeichi M, Mizuno K, Uemura T (2002) Control of actin reorganization by slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell 108:233–246

    PubMed  CAS  Google Scholar 

  51. Goyal P, Pandey D, Behring A, Siess W (2005) Inhibition of nuclear import of LIMK2 in endothelial cells by protein kinase C-dependent phosphorylation at Ser-283. J Biol Chem 280:27569–27577

    PubMed  CAS  Google Scholar 

  52. Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N (2003) p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus. J Biol Chem 278:52919–52923

    PubMed  CAS  Google Scholar 

  53. Lee S, Helfman DM (2004) Cytoplasmic p21Cip1 is involved in Ras-induced inhibition of the ROCK/LIMK/cofilin pathway. J Biol Chem 279:1885–1891

    PubMed  CAS  Google Scholar 

  54. Tanaka H, Yamashita T, Asada M, Mizutani S, Yoshikawa H, Tohyama M (2002) Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity. J Cell Biol 158:321–329

    PubMed  CAS  Google Scholar 

  55. Besson A, Assoian RK, Roberts JM (2004) Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nat Rev Cancer 4:948–955

    PubMed  CAS  Google Scholar 

  56. Chen X, Macara IG (2005) Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nat Cell Biol 7:262–269

    PubMed  CAS  Google Scholar 

  57. Hurd TW, Gao L, Roh MH, Macara IG, Margolis B (2003) Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol 5:137–142

    PubMed  CAS  Google Scholar 

  58. Chen X, Macara IG (2006) Par-3 mediates the inhibition of LIM kinase 2 to regulate cofilin phosphorylation and tight junction assembly. J Cell Biol 172:671–678

    PubMed  CAS  Google Scholar 

  59. Nagata-Ohashi K, Ohta Y, Goto K, Chiba S, Mori R, Nishita M, Ohashi K, Kousaka K, Iwamatsu A, Niwa R, Uemura T, Mizuno K (2004) A pathway of neuregulin-induced activation of cofilin-phosphatase slingshot and cofilin in lamellipodia. J Cell Biol 165:465–471

    PubMed  Google Scholar 

  60. St John MA, Tao W, Fei X, Fukumoto R, Carcangiu ML, Brownstein DG, Parlow AF, McGrath J, Xu T (1999) Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21:182–186

    PubMed  CAS  Google Scholar 

  61. Hisaoka M, Tanaka A, Hashimoto H (2002) Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest 82:1427–1435

    PubMed  CAS  Google Scholar 

  62. Morinaga N, Shitara Y, Yanagita Y, Koida T, Kimura M, Asao T, Kimijima I, Takenoshita S, Hirota T, Saya H, Kuwano H (2000) Molecular analysis of the h-warts/LATS1 gene in human breast cancer. Int J Oncol 17:1125–1129

    PubMed  CAS  Google Scholar 

  63. Yang X, Yu K, Hao Y, Li DM, Stewart R, Insogna KL, Xu T (2004) LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nat Cell Biol 6:609–617

    PubMed  CAS  Google Scholar 

  64. Amano T, Kaji N, Ohashi K, Mizuno K (2002) Mitosis-specific activation of LIM motif-containing protein kinase and roles of cofilin phosphorylation and dephosphorylation in mitosis. J Biol Chem 277:22093–22102

    PubMed  CAS  Google Scholar 

  65. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345

    PubMed  CAS  Google Scholar 

  66. Croft DR, Coleman ML, Li S, Robertson D, Sullivan T, Stewart CL, Olson MF (2005) Actin–myosin-based contraction is responsible for apoptotic nuclear disintegration. J Cell Biol 168:245–255

    PubMed  CAS  Google Scholar 

  67. Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J (2001) Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 3:346–352

    PubMed  CAS  Google Scholar 

  68. Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I (2005) The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 19:2307–2319

    PubMed  CAS  Google Scholar 

  69. Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289

    PubMed  CAS  Google Scholar 

  70. Nishimura Y, Yoshioka K, Bernard O, Himeno M, Itoh K (2004) LIM kinase 1: evidence for a role in the regulation of intracellular vesicle trafficking of lysosomes and endosomes in human breast cancer cells. Eur J Cell Biol 83:369–380

    PubMed  CAS  Google Scholar 

  71. Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K (2006) A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol 126:627–638

    PubMed  CAS  Google Scholar 

  72. Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jia Z (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121–133

    PubMed  CAS  Google Scholar 

  73. Meng Y, Takahashi H, Meng J, Zhang Y, Lu G, Asrar S, Nakamura T, Jia Z (2004) Regulation of ADF/cofilin phosphorylation and synaptic function by LIM-kinase. Neuropharmacology 47:746–754

    PubMed  CAS  Google Scholar 

  74. Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Caceres A (2004) LIMK1 regulates golgi dynamics, traffic of golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433–3449

    PubMed  CAS  Google Scholar 

  75. Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K (2003) Control of growth cone motility and morphology by LIM kinase and slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci 23:2527–2537

    PubMed  CAS  Google Scholar 

  76. Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, Ohashi K, Sekine-Aizawa Y, Sehara-Fujisawa A, Mizuno K, Goshima Y, Yahara I (2001) Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat Neurosci 4:367–373

    PubMed  CAS  Google Scholar 

  77. Heredia L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Caceres A, Lorenzo A (2006) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer’s disease. J Neurosci 26:6533–6542

    PubMed  CAS  Google Scholar 

  78. Lee-Hoeflich ST, Causing CG, Podkowa M, Zhao X, Wrana JL, Attisano L (2004) Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis. EMBO J 23:4792–4801

    PubMed  CAS  Google Scholar 

  79. Heredia L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Caceres A, Lorenzo A (2006) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer’s disease. J Neurosci 26:6533–6542

    PubMed  CAS  Google Scholar 

  80. Croft DR, Olson MF (2006) The Rho GTPase effector ROCK regulates cyclin A, cyclin D1 and p27Kip1 levels by distinct mechanisms. Mol Biol Cell 26:4612–4627

    CAS  Google Scholar 

  81. Sumi T, Matsumoto K, Nakamura T (2002) Mitosis-dependent phosphorylation and activation of LIM-kinase 1. Biochem Biophys Res Commun 290:1315–1320

    PubMed  CAS  Google Scholar 

  82. Kaji N, Ohashi K, Shuin M, Niwa R, Uemura T, Mizuno K (2003) Cell cycle-associated changes in slingshot phosphatase activity and roles in cytokinesis in animal cells. J Biol Chem 278:33450–33455

    PubMed  CAS  Google Scholar 

  83. Sumi T, Hashigasako A, Matsumoto K, Nakamura T (2006) Different activity regulation and subcellular localization of LIMK1 and LIMK2 during cell cycle transition. Exp Cell Res 312:1021–1030

    PubMed  CAS  Google Scholar 

  84. Sotiropoulos A, Gineitis D, Copeland J, Treisman R (1999) Signal-regulated activation of serum response factor is mediated by changes in actin dynamics. Cell 98:159–169

    PubMed  CAS  Google Scholar 

  85. Geneste O, Copeland JW, Treisman R (2002) LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics. J Cell Biol 157:831–838

    PubMed  CAS  Google Scholar 

  86. Miralles F, Posern G, Zaromytidou A-I, Treisman R (2003) Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113:329–342

    PubMed  CAS  Google Scholar 

  87. Joseph B, Wallen-Mackenzie A, Benoit G, Murata T, Joodmardi E, Okret S, Perlmann T (2003) p57(Kip2) cooperates with Nurr1 in developing dopamine cells. Proc Natl Acad Sci USA 100:15619–15624

    PubMed  CAS  Google Scholar 

  88. Ikebe C, Ohashi K, Mizuno K (1998) Identification of testis-specific (LIMK2t) and brain-specific (LIMK2c) isoforms of mouse LIM-kinase 2 gene transcripts. Biochem Biophys Res Commun 246:307–312

    PubMed  CAS  Google Scholar 

  89. Cheng AK, Robertson EJ (1995) The murine LIM-kinase gene (LIMk) encodes a novel serine threonine kinase expressed predominantly in trophoblast giant cells and the developing nervous system. Mech Dev 52:187–197

    PubMed  CAS  Google Scholar 

  90. Nomoto S, Tatematsu Y, Takahashi T, Osada H (1999) Cloning and characterization of the alternative promoter regions of the human LIMK2 gene responsible for alternative transcripts with tissue-specific expression. Gene 236:259–271

    PubMed  CAS  Google Scholar 

  91. Mori T, Okano I, Mizuno K, Tohyama M, Wanaka A (1997) Comparison of tissue distribution of two novel serine/threonine kinase genes containing the LIM motif (LIMK-1 and LIMK-2) in the developing rat. Mol Brain Res 45:247–254

    PubMed  CAS  Google Scholar 

  92. Foletta VC, Moussi N, Sarmiere PD, Bamburg JR, Bernard O (2004) LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic and adult tissues. Exp Cell Res 294:392–405

    PubMed  CAS  Google Scholar 

  93. Acevedo K, Moussi N, Li R, Soo P, Bernard O (2006) LIM kinase 2 is widely expressed in all tissues. J Histochem Cytochem 54:487–501

    PubMed  CAS  Google Scholar 

  94. Meyer-Lindenberg A, Mervis CB, Faith Berman K (2006) Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 7:380–393

    PubMed  CAS  Google Scholar 

  95. Hoogenraad CC, Koekkoek B, Akhmanova A, Krugers H, Dortland B, Miedema M, van Alphen A, Kistler WM, Jaegle M, Koutsourakis M, Van Camp N, Verhoye M, van der Linden A, Kaverina I, Grosveld F, De Zeeuw CI, Galjart N (2002) Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nat Genet 32:116–127

    PubMed  CAS  Google Scholar 

  96. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, Eichwald E, Keating MT (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393:276–280

    PubMed  CAS  Google Scholar 

  97. Li DY, Faury G, Taylor DG, Davis EC, Boyle WA, Mecham RP, Stenzel P, Boak B, Keating MT (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102:1783–1787

    Article  PubMed  CAS  Google Scholar 

  98. Takahashi H, Koshimizu U, Miyazaki J, Nakamura T (2002) Impaired spermatogenic ability of testicular germ cells in mice deficient in the LIM-kinase 2 gene. Dev Biol 241:259–272

    PubMed  CAS  Google Scholar 

  99. Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162:1089–1098

    PubMed  CAS  Google Scholar 

  100. Nishihara A, Watabe T, Imamura T, Miyazono K (2002) Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 13:3055–3063

    PubMed  CAS  Google Scholar 

  101. Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, Nakajima T, Inoue I (2001) Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 69:804–819

    PubMed  CAS  Google Scholar 

  102. Okamoto I, Pirker C, Bilban M, Berger W, Losert D, Marosi C, Haas OA, Wolff K, Pehamberger H (2005) Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma. Neoplasia 7:303–311

    PubMed  CAS  Google Scholar 

  103. Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R (2006) LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer 118:2703–2710

    PubMed  CAS  Google Scholar 

  104. Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E, Singer RH, Segall JE, Condeelis JS (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64:8585–8594

    PubMed  CAS  Google Scholar 

  105. Lee YJ, Mazzatti DJ, Yun Z, Keng PC (2005) Inhibition of invasiveness of human lung cancer cell line H1299 by over-expression of cofilin. Cell Biol Int 29:877–883

    PubMed  CAS  Google Scholar 

  106. Yap CT, Simpson TI, Pratt T, Price DJ, Maciver SK (2005) The motility of glioblastoma tumour cells is modulated by intracellular cofilin expression in a concentration-dependent manner. Cell Motil Cytoskeleton 60:153–165

    PubMed  CAS  Google Scholar 

  107. Zebda N, Bernard O, Bailly M, Welti S, Lawrence DS, Condeelis JS (2000) Phosphorylation of ADF/Cofilin abolishes EGF-induced actin nucleation at the leading edge and subsequent lamellipod extension. J Cell Biol 151:1119–1128

    PubMed  CAS  Google Scholar 

  108. Hotulainen P, Paunola E, Vartiainen MK, Lappalainen P (2005) Actin-depolymerizing factor and cofilin-1 play overlapping roles in promoting rapid F-actin depolymerization in mammalian nonmuscle cells. Mol Biol Cell 16:649–664

    PubMed  CAS  Google Scholar 

  109. Corpet F (1988) Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res 16:10881–10890

    PubMed  CAS  Google Scholar 

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Acknowledgement

The authors are supported by Cancer Research UK and by a grant from the National Institutes of Health to M.F.O. (R01 CA03072).

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  1. The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK

    Rebecca W. Scott & Michael F. Olson

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  1. Rebecca W. Scott
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  2. Michael F. Olson
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Correspondence to Michael F. Olson.

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Scott, R.W., Olson, M.F. LIM kinases: function, regulation and association with human disease. J Mol Med 85, 555–568 (2007). https://doi.org/10.1007/s00109-007-0165-6

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  • DOI: https://doi.org/10.1007/s00109-007-0165-6

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