Abstract
The RAS-RAF-MEK-extracellular-regulated kinase (RAS/ERK) pathway is a major intracellular route used by metazoan cells to channel to downstream targets a diverse array of signals, including those controlling cell proliferation and survival. Recent findings suggest that the pathway is assembled by specific scaffolding proteins that in turn regulate the efficiency, the location and/or the duration of signal transmission. Here, through the angle of studies conducted in Drosophila and C. elegans, we present two such proteins, the kinase suppressor of RAS (KSR) and connector enhancer of KSR (CNK) scaffolds, and highlight their implication in a novel mechanism regulating RAS-mediated RAF activation. Based on recent findings, we discuss the possibility that KSR, a RAF-like protein, does not solely act as a scaffold, but directly induces RAF catalytic function by a kinase-independent mechanism apparently shared by RAF-like proteins.
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References
Anselmo AN, Bumeister R, Thomas JM, White MA . (2002). Critical contribution of linker proteins to Raf kinase activation. J Biol Chem 277: 5940–5943.
Baonza A, Roch F, Martin-Blanco E . (2000). DER signaling restricts the boundaries of the wing field during Drosophila development. Proc Natl Acad Sci USA 97: 7331–7335.
Bell B, Xing H, Yan K, Gautam N, Muslin AJ . (1999). KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. J Biol Chem 274: 7982–7986.
Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR . (2006). Emerging roles of pseudokinases. Trends Cell Biol 16: 443–452.
Brtva TR, Drugan JK, Ghosh S, Terrell RS, Campbell-Burk S, Bell RM et al. (1995). Two distinct Raf domains mediate interaction with Ras. J Biol Chem 270: 9809–9812.
Bumeister R, Rosse C, Anselmo A, Camonis J, White MA . (2004). CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell differentiation. Curr Biol 14: 439–445.
Cabernard C, Affolter M . (2005). Distinct roles for two receptor tyrosine kinases in epithelial branching morphogenesis in Drosophila. Dev Cell 9: 831–842.
Cacace AM, Michaud NR, Therrien M, Mathes K, Copeland T, Rubin GM et al. (1999). Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol Cell Biol 19: 229–240.
Chadee DN, Xu D, Hung G, Andalibi A, Lim DJ, Luo Z et al. (2006). Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein. Proc Natl Acad Sci USA 103: 4463–4468.
Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL et al. (2003). Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17: 1263–1293.
Chang HC, Rubin GM . (1997). 14-3-3 epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev 11: 1132–1139.
Channavajhala PL, Rao VR, Spaulding V, Lin LL, Zhang YG . (2005). hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation. Biochem Biophys Res Commun 334: 1214–1218.
Channavajhala PL, Wu L, Cuozzo JW, Hall JP, Liu W, Lin LL et al. (2003). Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. J Biol Chem 278: 47089–47097.
Chiloeches A, Mason CS, Marais R . (2001). S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Mol Cell Biol 21: 2423–2434.
Chong H, Lee J, Guan KL . (2001). Positive and negative regulation of Raf kinase activity and function by phosphorylation. EMBO J 20: 3716–3727.
Chong H, Vikis HG, Guan KL . (2003). Mechanisms of regulating the Raf kinase family. Cell Signal 15: 463–469.
Colon-Gonzalez F, Kazanietz MG . (2006). C1 domains exposed: from diacylglycerol binding to protein-protein interactions. Biochim Biophys Acta 1761: 827–837.
Cutler Jr RE, Stephens RM, Saracino MR, Morrison DK . (1998). Autoregulation of the Raf-1 serine/threonine kinase. Proc Natl Acad Sci USA 95: 9214–9219.
Dard N, Peter M . (2006). Scaffold proteins in MAP kinase signaling: more than simple passive activating platforms. Bioessays 28: 146–156.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417: 949–954.
Denouel-Galy A, Douville EM, Warne PH, Papin C, Laugier D, Calothy G et al. (1998). Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr Biol 8: 46–55.
Dhillon AS, Kolch W . (2002). Untying the regulation of the Raf-1 kinase. Arch Biochem Biophys 404: 3–9.
Dhillon AS, Meikle S, Yazici Z, Eulitz M, Kolch W . (2002a). Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J 21: 64–71.
Dhillon AS, Pollock C, Steen H, Shaw PE, Mischak H, Kolch W . (2002b). Cyclic AMP-dependent kinase regulates Raf-1 kinase mainly by phosphorylation of serine 259. Mol Cell Biol 22: 3237–3246.
Douziech M, Roy F, Laberge G, Lefrancois M, Armengod AV, Therrien M . (2003). KSR is a scaffold required for activation of the ERK/MAPK module. EMBO J 22: 5068–5078.
Douziech M, Sahmi M, Laberge G, Therrien M . (2006). A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes Dev 20: 807–819.
Dumaz N, Marais R . (2003). Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. J Biol Chem 278: 29819–29823.
English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S et al. (1999). New insights into the control of MAP kinase pathways. Exp Cell Res 253: 255–270.
Fabian JR, Daar IO, Morrison DK . (1993). Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol Cell Biol 13: 7170–7179.
Farrar MA, Alberol I, Perlmutter RM . (1996). Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature 383: 178–181.
Friedman A, Perrimon N . (2006). A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature 444: 230–234.
Fritz RD, Radziwill G . (2005). The scaffold protein CNK1 interacts with the angiotensin II type 2 receptor. Biochem Biophys Res Commun 338: 1906–1912.
Garnett MJ, Rana S, Paterson H, Barford D, Marais R . (2005). Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20: 963–969.
Gollob JA, Wilhelm S, Carter C, Kelley SL . (2006). Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol 33: 392–406.
Hanks SK, Quinn AM, Hunter T . (1988). The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241: 42–52.
Hu CD, Kariya K, Tamada M, Akasaka K, Shirouzu M, Yokoyama S et al. (1995). Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras. J Biol Chem 270: 30274–30277.
Huwiler A, Brunner J, Hummel R, Vervoordeldonk M, Stabel S, van den Bosch H et al. (1996). Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. Proc Natl Acad Sci USA 93: 6959–6963.
Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K . (1999). Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev 13: 163–175.
Jaffe AB, Aspenstrom P, Hall A . (2004). Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Mol Cell Biol 24: 1736–1746.
Jaffe AB, Hall A, Schmidt A . (2005). Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho. Curr Biol 15: 405–412.
Jaumot M, Hancock JF . (2001). Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene 20: 3949–3958.
Kao G, Tuck S, Baillie D, Sundaram MV . (2004). C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites. Development 131: 755–765.
Kolch W . (2000). Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351 (Part 2): 289–305.
Kolch W . (2005). Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6: 827–837.
Kornfeld K, Hom DB, Horvitz HR . (1995). The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 83: 903–913.
Kremer NE, D'Arcangelo G, Thomas SM, DeMarco M, Brugge JS, Halegoua S . (1991). Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J Cell Biol 115: 809–819.
Krugmann S, Anderson KE, Ridley SH, Risso N, McGregor A, Coadwell J et al. (2002). Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol Cell 9: 95–108.
Laberge G, Douziech M, Therrien M . (2005). Src42 binding activity regulates Drosophila RAF by a novel CNK-dependent derepression mechanism. EMBO J 24: 487–498.
Lanigan TM, Liu A, Huang YZ, Mei L, Margolis B, Guan KL . (2003). Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. FASEB J 17: 2048–2060.
Lemmon MA . (2004). Pleckstrin homology domains: not just for phosphoinositides. Biochem Soc Trans 32: 707–711.
Li W, Skoulakis EM, Davis RL, Perrimon N . (1997). The Drosophila 14-3-3 protein Leonardo enhances Torso signaling through D-Raf in a Ras 1-dependent manner. Development 124: 4163–4171.
Lopez-Ilasaca MA, Bernabe-Ortiz JC, Na SY, Dzau VJ, Xavier RJ . (2005). Bioluminescence resonance energy transfer identify scaffold protein CNK1 interactions in intact cells. FEBS Lett 579: 648–654.
Luo Z, Diaz B, Marshall MS, Avruch J . (1997). An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ. Mol Cell Biol 17: 46–53.
Luo Z, Tzivion G, Belshaw PJ, Vavvas D, Marshall M, Avruch J . (1996). Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature 383: 181–185.
Manning G, Plowman GD, Hunter T, Sudarsanam S . (2002). Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 27: 514–520.
Marais R, Light Y, Paterson HF, Marshall CJ . (1995). Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14: 3136–3145.
Marais R, Light Y, Paterson HF, Mason CS, Marshall CJ . (1997). Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases. J Biol Chem 272: 4378–4383.
Mason CS, Springer CJ, Cooper RG, Superti-Furga G, Marshall CJ, Marais R . (1999). Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. EMBO J 18: 2137–2148.
Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA . (2004). Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427: 256–260.
Michaud NR, Therrien M, Cacace A, Edsall LC, Spiegel S, Rubin GM et al. (1997). KSR stimulates Raf-1 activity in a kinase-independent manner. Proc Natl Acad Sci USA 94: 12792–12796.
Morrison DK, Heidecker G, Rapp UR, Copeland TD . (1993). Identification of the major phosphorylation sites of the Raf-1 kinase. J Biol Chem 268: 17309–17316.
Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL . (1996). The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site. Proc Natl Acad Sci USA 93: 8312–8317.
Muller J, Cacace AM, Lyons WE, McGill CB, Morrison DK . (2000). Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling. Mol Cell Biol 20: 5529–5539.
Muller J, Ory S, Copeland T, Piwnica-Worms H, Morrison DK . (2001). C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell 8: 983–993.
Muslin AJ, Tanner JW, Allen PM, Shaw AS . (1996). Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84: 889–897.
Nguyen A, Burack WR, Stock JL, Kortum R, Chaika OV, Afkarian M et al. (2002). Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol Cell Biol 22: 3035–3045.
Nourry C, Grant SG, Borg JP . (2003). PDZ domain proteins: plug and play!. Sci STKE (2003: re7).
Ohmachi M, Rocheleau CE, Church D, Lambie E, Schedl T, Sundaram MV . (2002). C. elegans ksr-1 and ksr-2 have both unique and redundant functions and are required for MPK-1 ERK phosphorylation. Curr Biol 12: 427–433.
Ohtakara K, Nishizawa M, Izawa I, Hata Y, Matsushima S, Taki W et al. (2002). Densin-180, a synaptic protein, links to PSD-95 through its direct interaction with MAGUIN-1. Genes Cells 7: 1149–1160.
Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK . (2003). Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 13: 1356–1364.
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153–183.
Qiao F, Bowie JU . (2005). The many faces of SAM. Sci STKE 2005: re7.
Rabizadeh S, Xavier RJ, Ishiguro K, Bernabeortiz J, Lopez-Ilasaca M, Khokhlatchev A et al. (2004). The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. J Biol Chem 279: 29247–29254.
Robinson MJ, Harkins PC, Zhang J, Baer R, Haycock JW, Cobb MH et al. (1996). Mutation of position 52 in ERK2 creates a nonproductive binding mode for adenosine 5′-triphosphate. Biochemistry 35: 5641–5646.
Rocheleau CE, Ronnlund A, Tuck S, Sundaram MV . (2005). Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling. Proc Natl Acad Sci USA 102: 11757–11762.
Roignant JY, Hamel S, Janody F, Treisman JE . (2006). The novel SAM domain protein Aveugle is required for Raf activation in the Drosophila EGF receptor signaling pathway. Genes Dev 20: 795–806.
Rommel C, Radziwill G, Lovric J, Noeldeke J, Heinicke T, Jones D et al. (1996). Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1. Oncogene 12: 609–619.
Rommel C, Radziwill G, Moelling K, Hafen E . (1997). Negative regulation of Raf activity by binding of 14-3-3 to the amino terminus of Raf in vivo. Mech Dev 64: 95–104.
Roy F, Laberge G, Douziech M, Ferland-McCollough D, Therrien M . (2002). KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev 16: 427–438.
Roy S, Lane A, Yan J, McPherson R, Hancock JF . (1997). Activity of plasma membrane-recruited Raf-1 is regulated by Ras via the Raf zinc finger. J Biol Chem 272: 20139–20145.
Rushworth LK, Hindley AD, O'Neill E, Kolch W . (2006). Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol 26: 2262–2272.
Schaeffer HJ, Weber MJ . (1999). Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19: 2435–2444.
Sieburth DS, Sun Q, Han M . (1998). SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans. Cell 94: 119–130.
Stewart S, Sundaram M, Zhang Y, Lee J, Han M, Guan KL . (1999). Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol Cell Biol 19: 5523–5534.
Sugimoto T, Stewart S, Han M, Guan KL . (1998). The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation. EMBO J 17: 1717–1727.
Sundaram M, Han M . (1995). The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83: 889–901.
Terai K, Matsuda M . (2006). The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J 25: 3556–3564.
Therrien M, Chang HC, Solomon NM, Karim FD, Wassarman DA, Rubin GM . (1995). KSR, a novel protein kinase required for RAS signal transduction. Cell 83: 879–888.
Therrien M, Michaud NR, Rubin GM, Morrison DK . (1996). KSR modulates signal propagation within the MAPK cascade. Genes Dev 10: 2684–2695.
Therrien M, Wong AM, Rubin GM . (1998). CNK, a RAF-binding multidomain protein required for RAS signaling. Cell 95: 343–353.
Therrien M, Wong AM, Kwan E, Rubin GM . (1999). Functional analysis of CNK in RAS signaling. Proc Natl Acad Sci USA 96: 13259–13263.
Torii S, Nakayama K, Yamamoto T, Nishida E . (2004). Regulatory mechanisms and function of ERK MAP kinases. J Biochem (Tokyo) 136: 557–561.
Tsuda L, Inoue YH, Yoo MA, Mizuno M, Hata M, Lim YM et al. (1993). A protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila. Cell 72: 407–414.
Vaillancourt RR, Gardner AM, Johnson GL . (1994). B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. Mol Cell Biol 14: 6522–6530.
Vaudry D, Stork PJ, Lazarovici P, Eiden LE . (2002). B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. Science 296: 1648–1649.
Venkateswarlu K . (2003). Interaction protein for cytohesin exchange factors 1 (IPCEF1) binds cytohesin 2 and modifies its activity. J Biol Chem 278: 43460–43469.
von Kriegsheim A, Pitt A, Grindlay GJ, Kolch W, Dhillon AS . (2006). Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5. Nat Cell Biol 8: 1011–1016.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM et al. (2004). Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116: 855–867.
Wassarman DA, Solomon NM, Chang HC, Karim FD, Therrien M, Rubin GM . (1996). Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila. Genes Dev 10: 272–278.
Weber CK, Slupsky JR, Kalmes HA, Rapp UR . (2001). Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res 61: 3595–3598.
Wellbrock C, Karasarides M, Marais R . (2004). The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5: 875–885.
Werry TD, Christopoulos A, Sexton PM . (2006). Mechanisms of ERK1/2 regulation by seven-transmembrane-domain receptors. Curr Pharm Des 12: 1683–1702.
Widmann C, Gibson S, Jarpe MB, Johnson GL . (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79: 143–180.
Williams JG, Drugan JK, Yi GS, Clark GJ, Der CJ, Campbell SL . (2000). Elucidation of binding determinants and functional consequences of Ras/Raf-cysteine-rich domain interactions. J Biol Chem 275: 22172–22179.
Xing H, Kornfeld K, Muslin AJ . (1997). The protein kinase KSR interacts with 14-3-3 protein and Raf. Curr Biol 7: 294–300.
Xu B, English JM, Wilsbacher JL, Stippec S, Goldsmith EJ, Cobb MH . (2000). WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. J Biol Chem 275: 16795–16801.
Yan F, Polk DB . (2001). Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. Cancer Res 61: 963–969.
Yao I, Hata Y, Ide N, Hirao K, Deguchi M, Nishioka H et al. (1999). MAGUIN, a novel neuronal membrane-associated guanylate kinase-interacting protein. J Biol Chem 274: 11889–11896.
Yao I, Ohtsuka T, Kawabe H, Matsuura Y, Takai Y, Hata Y . (2000). Association of membrane-associated guanylate kinase-interacting protein-1 with Raf-1. Biochem Biophys Res Commun 270: 538–542.
Yoder JH, Chong H, Guan KL, Han M . (2004). Modulation of KSR activity in Caenorhabditis elegans by Zn ions, qPAR-1 kinase and PP2A phosphatase. EMBO J 23: 111–119.
Yu W, Fantl WJ, Harrowe G, Williams LT . (1998). Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr Biol 8: 56–64.
Zhang BH, Guan KL . (2000). Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601. EMBO J 19: 5429–5439.
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J . (2006). An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125: 1137–1149.
Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S et al. (1997). Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89: 63–72.
Zhou M, Horita DA, Waugh DS, Byrd RA, Morrison DK . (2002). Solution structure and functional analysis of the cysteine-rich C1 domain of kinase suppressor of Ras (KSR). J Mol Biol 315: 435–446.
Zimmermann S, Moelling K . (1999). Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286: 1741–1744.
Ziogas A, Moelling K, Radziwill G . (2005). CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. J Biol Chem 280: 24205–24211.
Acknowledgements
We thank Dariel Ashton-Beaucage and Gino Laberge for helpful discussions and critical reading of the paper. AC is supported by a fellowship from La Fondation pour la Recherche Médicale (FRM; France) and MT is recipient of a Canadian Research Chair. This work was supported by grants from the Canadian Institutes of Health Research and the National Cancer Institute of Canada with funds from the Canadian Cancer Society.
