Abstract
Cells respond to changes in their environment, to developmental cues, and to pathogen aggression through the action of a complex network of proteins. These networks can be decomposed into a multitude of signaling pathways that relay signals from the microenvironment to the cellular components involved in eliciting a specific response. Perturbations in these signaling processes are at the root of multiple pathologies, the most notable of these being cancer. The study of receptor tyrosine kinase (RTK) signaling led to the first description of a mechanism whereby an extracellular signal is transmitted to the nucleus to induce a transcriptional response. Genetic studies conducted in drosophila and nematodes have provided key elements to this puzzle. Here, we briefly discuss the somewhat lesser known contribution of these multicellular organisms to our understanding of what has come to be known as the prototype of signaling pathways. We also discuss the ostensibly much larger network of regulators that has emerged from recent functional genomic investigations of RTK/RAS/ERK signaling.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310
Kamata T, Feramisco JR (1984) Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310:147–150
Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–465
Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6(11):827–837
McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26(22):3113–3121
Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308
Zebisch A, Czernilofsky AP, Keri G et al (2007) Signaling through RAS-RAF-MEK-ERK: from basics to bedside. Curr Med Chem 14:601–623
Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9(7):517–531
Lavoie H, Therrien M (2015) Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 16:281–298
Turjanski AG, Vaque JP, Gutkind JS (2007) MAP kinases and the control of nuclear events. Oncogene 26(22):3240–3253
Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68(2):320–344
Wortzel I, Seger R (2011) The ERK cascade: distinct functions within various subcellular organelles. Genes Cancer 2:195–209
Yoon S, Seger R (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24:21–44
Roskoski R Jr (2012) ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66:105–143
Han M, Sternberg PW (1990) let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Cell 63:921–931
Beitel GJ, Clark SG, Horvitz HR (1990) Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction. Nature 348:503–509
Simon MA, Bowtell DD, Dodson GS et al (1991) Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell 67:701–716
Mulcahy LS, Smith MR, Stacey DW (1985) Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313:241–243
Downward J, Riehl R, Wu L et al (1990) Identification of a nucleotide exchange-promoting activity for p21ras. Proc Natl Acad Sci U S A 87:5998–6002
Wolfman A, Macara IG (1990) A cytosolic protein catalyzes the release of GDP from p21ras. Science 248:67–69
Bonfini L, Karlovich CA, Dasgupta C et al (1992) The Son of sevenless gene product: a putative activator of Ras. Science 255:603–606
Rogge RD, Karlovich CA, Banerjee U (1991) Genetic dissection of a neurodevelopmental pathway: Son of sevenless functions downstream of the sevenless and EGF receptor tyrosine kinases. Cell 64:39–48
Robinson LC, Gibbs JB, Marshall MS et al (1987) CDC25: a component of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235:1218–1221
Broek D, Toda T, Michaeli T et al (1987) The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell 48:789–799
Bowtell D, Fu P, Simon M et al (1992) Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc Natl Acad Sci U S A 89:6511–6515
Shou C, Farnsworth CL, Neel BG et al (1992) Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature 358:351–354
Wei W, Mosteller RD, Sanyal P et al (1992) Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 89:7100–7104
Martegani E, Vanoni M, Zippel R et al (1992) Cloning by functional complementation of a mouse cDNA encoding a homologue of CDC25, a Saccharomyces cerevisiae RAS activator. EMBO J 11:2151–2157
Clark SG, Stern MJ, Horvitz HR (1992) C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Nature 356:340–344
Buday L, Downward J (1993) Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73:611–620
Chardin P, Camonis JH, Gale NW et al (1993) Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260(5112):1338–1343
Egan SE, Giddings BW, Brooks MW et al (1993) Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363:45–51
Gale NW, Kaplan S, Lowenstein EJ et al (1993) Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363:88–92
Li N, Batzer A, Daly R et al (1993) Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363:85–88
Olivier JP, Raabe T, Henkemeyer M et al (1993) A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell 73:179–191
Rozakis-Adcock M, Fernley R, Wade J et al (1993) The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363:83–85
Simon MA, Dodson GS, Rubin GM (1993) An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell 73:169–177
Vogel US, Dixon RA, Schaber MD et al (1988) Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335:90–93
Ballester R, Marchuk D, Boguski M et al (1990) The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63:851–859
Trahey M, Wong G, Halenbeck R et al (1988) Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242:1697–1700
Adari H, Lowy DR, Willumsen BM et al (1988) Guanosine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain. Science 240:518–521
Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542–545
Xu GF, O'Connell P, Viskochil D et al (1990) The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62:599–608
Martin GA, Viskochil D, Bollag G et al (1990) The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843–849
Gaul U, Mardon G, Rubin GM (1992) A putative Ras GTPase activating protein acts as a negative regulator of signaling by the Sevenless receptor tyrosine kinase. Cell 68:1007–1019
Smith MR, DeGudicibus SJ, Stacey DW (1986) Requirement for c-ras proteins during viral oncogene transformation. Nature 320:540–543
Kolch W, Heidecker G, Lloyd P et al (1991) Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature 349:426–428
Rapp UR, Todaro GJ (1980) Generation of oncogenic mouse type C viruses: in vitro selection of carcinoma-inducing variants. Proc Natl Acad Sci U S A 77:624–628
Rapp UR, Goldsborough MD, Mark GE et al (1983) Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci U S A 80:4218–4222
Bonner T, O'Brien SJ, Nash WG et al (1984) The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4. Science 223:71–74
Ishikawa F, Takaku F, Ochiai M et al (1985) Activated c-raf gene in a rat hepatocellular carcinoma induced by 2-amino-3-methylimidazo[4,5-f]quinoline. Biochem Biophys Res Commun 132:186–192
Kozak C, Gunnell MA, Rapp UR (1984) A new oncogene, c-raf, is located on mouse chromosome 6. J Virol 49:297–299
Bonner TI, Kerby SB, Sutrave P et al (1985) Structure and biological activity of human homologs of the raf/mil oncogene. Mol Cell Biol 5:1400–1407
Dickson B, Sprenger F, Morrison D et al (1992) Raf functions downstream of Ras1 in the Sevenless signal transduction pathway. Nature 360:600–603
Han M, Golden A, Han Y et al (1993) C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 363:133–140
Cutforth T, Rubin GM (1994) Mutations in Hsp83 and cdc37 impair signaling by the sevenless receptor tyrosine kinase in Drosophila. Cell 77:1027–1036
van der Straten A, Rommel C, Dickson B et al (1997) The heat shock protein 83 (Hsp83) is required for Raf-mediated signalling in Drosophila. EMBO J 16:1961–1969
Schulte TW, Blagosklonny MV, Ingui C et al (1995) Disruption of the Raf-1-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association. J Biol Chem 270:24585–24588
Grammatikakis N, Lin JH, Grammatikakis A et al (1999) p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Mol Cell Biol 19:1661–1672
Tsuda L, Inoue YH, Yoo MA et al (1993) A protein kinase similar to MAP kinase activator acts downstream of the raf kinase in Drosophila. Cell 72:407–414
Crews CM, Erikson RL (1992) Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product. Proc Natl Acad Sci U S A 89:8205–8209
Kyriakis JM, App H, Zhang XF et al (1992) Raf-1 activates MAP kinase-kinase. Nature 358:417–421
Wu Y, Han M, Guan KL (1995) MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Genes Dev 9:742–755
Kornfeld K, Guan KL, Horvitz HR (1995) The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. Genes Dev 9:756–768
Biggs WH 3rd, Zavitz KH, Dickson B et al (1994) The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway. EMBO J 13:1628–1635
Biggs WH 3rd, Zipursky SL (1992) Primary structure, expression, and signal-dependent tyrosine phosphorylation of a Drosophila homolog of extracellular signal-regulated kinase. Proc Natl Acad Sci U S A 89:6295–6299
Lackner MR, Kornfeld K, Miller LM et al (1994) A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in Caenorhabditis elegans. Genes Dev 8:160–173
Wu Y, Han M (1994) Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Genes Dev 8:147–159
Boulton TG, Nye SH, Robbins DJ et al (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65:663–675
Boulton TG, Gregory JS, Cobb MH (1991) Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase. Biochemistry 30:278–286
Perkins LA, Larsen I, Perrimon N (1992) corkscrew encodes a putative protein tyrosine phosphatase that functions to transduce the terminal signal from the receptor tyrosine kinase torso. Cell 70:225–236
Raabe T, Riesgo-Escovar J, Liu X et al (1996) DOS, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in Drosophila. Cell 85:911–920
Herbst R, Zhang X, Qin J et al (1999) Recruitment of the protein tyrosine phosphatase CSW by DOS is an essential step during signaling by the sevenless receptor tyrosine kinase. EMBO J 18:6950–6961
Cleghon V, Feldmann P, Ghiglione C et al (1998) Opposing actions of CSW and RasGAP modulate the strength of Torso RTK signaling in the Drosophila terminal pathway. Mol Cell 2:719–727
Chong ZZ, Maiese K (2007) The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol 22:1251–1267
Hacohen N, Kramer S, Sutherland D et al (1998) sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92:253–263
Casci T, Vinos J, Freeman M (1999) Sprouty, an intracellular inhibitor of Ras signaling. Cell 96:655–665
Reich A, Sapir A, Shilo B (1999) Sprouty is a general inhibitor of receptor tyrosine kinase signaling. Development 126:4139–4147
Sasaki A, Taketomi T, Kato R et al (2003) Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nat Cell Biol 5:427–432
Gross I, Bassit B, Benezra M et al (2001) Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem 276:46460–46468
Hanafusa H, Torii S, Yasunaga T et al (2002) Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 4:850–858
Tefft D, Lee M, Smith S et al (2002) mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins. Am J Physiol Lung Cell Mol Physiol 283:L700–L706
Jarvis LA, Toering SJ, Simon MA et al (2006) Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases. Development 133:1133–1142
Hanafusa H, Torii S, Yasunaga T et al (2004) Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. J Biol Chem 279:22992–22995
Kim HJ, Taylor LJ, Bar-Sagi D (2007) Spatial regulation of EGFR signaling by Sprouty2. Curr Biol 17:455–461
Sieglitz F, Matzat T, Yuva-Aydemir Y et al (2013) Antagonistic feedback loops involving Rau and Sprouty in the Drosophila eye control neuronal and glial differentiation. Sci Signal 6:ra96
Dikic I, Schmidt MH (2007) Malfunctions within the Cbl interactome uncouple receptor tyrosine kinases from destructive transport. Eur J Cell Biol 86:505–512
Yoon CH, Lee J, Jongeward GD et al (1995) Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl. Science 269:1102–1105
Wong ES, Lim J, Low BC et al (2001) Evidence for direct interaction between Sprouty and Cbl. J Biol Chem 276:5866–5875
Fong CW, Leong HF, Wong ES et al (2003) Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem 278:33456–33464
Hall AB, Jura N, DaSilva J et al (2003) hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl. Curr Biol 13:308–314
Rubin C, Litvak V, Medvedovsky H et al (2003) Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops. Curr Biol 13:297–307
Wong ES, Fong CW, Lim J et al (2002) Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. EMBO J 21:4796–4808
Egan JE, Hall AB, Yatsula BA et al (2002) The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A 99:6041–6046
Miura GI, Roignant JY, Wassef M et al (2008) Myopic acts in the endocytic pathway to enhance signaling by the Drosophila EGF receptor. Development 135:1913–1922
Tanase CA (2010) Histidine domain-protein tyrosine phosphatase interacts with Grb2 and GrpL. PLoS One 5:e14339
Kim HJ, Bar-Sagi D (2004) Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 5:441–450
Vojtek AB, Hollenberg SM, Cooper JA (1993) Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74:205–214
Warne PH, Viciana PR, Downward J (1993) Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364:352–355
Moodie SA, Willumsen BM, Weber MJ et al (1993) Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260:1658–1661
Zhang XF, Settleman J, Kyriakis JM et al (1993) Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364:308–313
Hughes DA, Ashworth A, Marshall CJ (1993) Complementation of byr1 in fission yeast by mammalian MAP kinase kinase requires coexpression of Raf kinase. Nature 364:349–352
Howe LR, Leevers SJ, Gomez N et al (1992) Activation of the MAP kinase pathway by the protein kinase raf. Cell 71:335–342
Errede B, Levin DE (1993) A conserved kinase cascade for MAP kinase activation in yeast. Curr Opin Cell Biol 5:254–260
Pelech SL, Sanghera JS (1992) Mitogen-activated protein kinases: versatile transducers for cell signaling. Trends Biochem Sci 17:233–238
Campbell SL, Khosravi-Far R, Rossman KL et al (1998) Increasing complexity of Ras signaling. Oncogene 17:1395–1413
Carlson SM, Chouinard CR, Labadorf A et al (2011) Large-scale discovery of ERK2 substrates identifies ERK-mediated transcriptional regulation by ETV3. Sci Signal 4:rs11
Kosako H, Yamaguchi N, Aranami C et al (2009) Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport. Nat Struct Mol Biol 16:1026–1035
Old WM, Shabb JB, Houel S et al (2009) Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Mol Cell 34:115–131
Courcelles M, Fremin C, Voisin L et al (2013) Phosphoproteome dynamics reveal novel ERK1/2 MAP kinase substrates with broad spectrum of functions. Mol Syst Biol 9:669
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
Therrien M, Chang HC, Solomon NM et al (1995) KSR, a novel protein kinase required for RAS signal transduction. Cell 83:879–888
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
Douziech M, Sahmi M, Laberge G et al (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
Stewart S, Sundaram M, Zhang Y et al (1999) Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol Cell Biol 19:5523–5534
Roy F, Laberge G, Douziech M et al (2002) KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev 16:427–438
Anselmo AN, Bumeister R, Thomas JM et al (2002) Critical contribution of linker proteins to Raf kinase activation. J Biol Chem 277:5940–5943
Lozano J, Xing R, Cai Z et al (2003) Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res 63:4232–4238
Nguyen A, Burack WR, Stock JL 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
Therrien M, Michaud NR, Rubin GM et al (1996) KSR modulates signal propagation within the MAPK cascade. Genes Dev 10:2684–2695
Xing H, Kornfeld K, Muslin AJ (1997) The protein kinase KSR interacts with 14-3-3 protein and Raf. Curr Biol 7:294–300
Denouel-Galy A, Douville EM, Warne PH et al (1998) Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr Biol 8:46–55
Yu W, Fantl WJ, Harrowe G et al (1998) Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr Biol 8:56–64
Cacace AM, Michaud NR, Therrien M 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
Yan F, John SK, Wilson G et al (2004) Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation. J Clin Invest 114:1272–1280
Hu J, Yu H, Kornev AP et al (2011) Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF. Proc Natl Acad Sci U S A 108:6067–6072
Therrien M, Wong AM, Rubin GM (1998) CNK, a RAF-binding multidomain protein required for RAS signaling. Cell 95:343–353
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
Roignant JY, Hamel S, Janody F et al (2006) The novel SAM domain protein Aveugle is required for Raf activation in the Drosophila EGF receptor signaling pathway. Genes Dev 20:795–806
Rajakulendran T, Sahmi M, Kurinov I et al (2008) CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling. Proc Natl Acad Sci U S A 105:2836–2841
Hahn I, Fuss B, Peters A et al (2013) The Drosophila Arf GEF Steppke controls MAPK activation in EGFR signaling. J Cell Sci 126:2470–2479
Rajakulendran T, Sahmi M, Lefrancois M et al (2009) A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461:542–545
Lavoie H, Therrien M (2010) It takes two RAFs to tango. Med Sci (Paris) 26:459–460
Lanigan TM, Liu A, Huang YZ et al (2003) Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. FASEB J 17:2048–2060
Bumeister R, Rosse C, Anselmo A et al (2004) CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell differentiation. Curr Biol 14:439–445
Yao I, Ohtsuka T, Kawabe H et al (2000) Association of membrane-associated guanylate kinase-interacting protein-1 with Raf-1. Biochem Biophys Res Commun 270:538–542
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
Gringhuis SI, den Dunnen J, Litjens M et al (2009) Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 10:1081–1088
Claperon A, Therrien M (2007) KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene 26:3143–3158
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
Selfors LM, Schutzman JL, Borland CZ et al (1998) soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling. Proc Natl Acad Sci U S A 95:6903–6908
Li W, Han M, Guan KL (2000) The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev 14:895–900
Rodriguez-Viciana P, Oses-Prieto J, Burlingame A et al (2006) A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell 22:217–230
Gu T, Orita S, Han M (1998) Caenorhabditis elegans SUR-5, a novel but conserved protein, negatively regulates LET-60 Ras activity during vulval induction. Mol Cell Biol 18:4556–4564
Wassarman DA, Solomon NM, Chang HC et al (1996) Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila. Genes Dev 10:272–278
Dougherty MK, Morrison DK (2004) Unlocking the code of 14-3-3. J Cell Sci 117:1875–1884
Jaumot M, Hancock JF (2001) Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions. Oncogene 20:3949–3958
Tzivion G, Luo Z, Avruch J (1998) A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature 394:88–92
Kockel L, Vorbruggen G, Jackle H et al (1997) Requirement for Drosophila 14-3-3 zeta in Raf-dependent photoreceptor development. Genes Dev 11:1140–1147
Chang HC, Rubin GM (1997) 14-3-3 Epsilon positively regulates Ras-mediated signaling in Drosophila. Genes Dev 11:1132–1139
Freed E, Symons M, Macdonald SG et al (1994) Binding of 14-3-3 proteins to the protein kinase Raf and effects on its activation. Science 265:1713–1716
Irie K, Gotoh Y, Yashar BM et al (1994) Stimulatory effects of yeast and mammalian 14-3-3 proteins on the Raf protein kinase. Science 265:1716–1719
Sieburth DS, Sundaram M, Howard RM et al (1999) A PP2A regulatory subunit positively regulates Ras-mediated signaling during Caenorhabditis elegans vulval induction. Genes Dev 13:2562–2569
Yoder JH, Chong H, Guan KL et al (2004) Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase. EMBO J 23:111–119
Karim FD, Chang HC, Therrien M et al (1996) A screen for genes that function downstream of Ras1 during Drosophila eye development. Genetics 143:315–329
Pulido R, Zuniga A, Ullrich A (1998) PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J 17:7337–7350
Karim FD, Rubin GM (1999) PTP-ER, a novel tyrosine phosphatase, functions downstream of Ras1 to downregulate MAP kinase during Drosophila eye development. Mol Cell 3:741–750
Blanco-Aparicio C, Torres J, Pulido R (1999) A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. J Cell Biol 147:1129–1136
Lee WJ, Kim SH, Kim YS et al (2000) Inhibition of mitogen-activated protein kinase by a Drosophila dual-specific phosphatase. Biochem J 349:821–828
Reiterer V, Fey D, Kolch W et al (2013) Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2. Proc Natl Acad Sci U S A 110:E2934–E2943
Berset T, Hoier EF, Battu G et al (2001) Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science 291:1055–1058
Kim SH, Kwon HB, Kim YS et al (2002) Isolation and characterization of a Drosophila homologue of mitogen-activated protein kinase phosphatase-3 which has a high substrate specificity towards extracellular-signal-regulated kinase. Biochem J 361:143–151
Rintelen F, Hafen E, Nairz K (2003) The Drosophila dual-specificity ERK phosphatase DMKP3 cooperates with the ERK tyrosine phosphatase PTP-ER. Development 130:3479–3490
Gomez AR, Lopez-Varea A, Molnar C et al (2005) Conserved cross-interactions in Drosophila and Xenopus between Ras/MAPK signaling and the dual-specificity phosphatase MKP3. Dev Dyn 232:695–708
Molnar C, de Celis JF (2013) Tay bridge is a negative regulator of EGFR signalling and interacts with Erk and Mkp3 in the Drosophila melanogaster wing. PLoS Genet 9:e1003982
Baril C, Therrien M (2006) Alphabet, a Ser/Thr phosphatase of the protein phosphatase 2C family, negatively regulates RAS/MAPK signaling in Drosophila. Dev Biol 294:232–245
Baril C, Sahmi M, Ashton-Beaucage D et al (2009) The PP2C alphabet is a negative regulator of stress-activated protein kinase signaling in Drosophila. Genetics 181:567–579
Shohat M, Ben-Meir D, Lavi S (2012) Protein phosphatase magnesium dependent 1A (PPM1A) plays a role in the differentiation and survival processes of nerve cells. PLoS One 7:e32438
Li R, Gong Z, Pan C et al (2013) Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase. FEBS J 280:2700–2711
Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647
Lee MH, Hook B, Pan G et al (2007) Conserved regulation of MAP kinase expression by PUF RNA-binding proteins. PLoS Genet 3:e233
Kim SY, Kim JY, Malik S et al (2012) Negative regulation of EGFR/MAPK pathway by Pumilio in Drosophila melanogaster. PLoS One 7:e34016
Ashton-Beaucage D, Udell CM, Lavoie H et al (2010) The exon junction complex controls the splicing of MAPK and other long intron-containing transcripts in Drosophila. Cell 143:251–262
Roignant JY, Treisman JE (2010) Exon junction complex subunits are required to splice Drosophila MAP kinase, a large heterochromatic gene. Cell 143:238–250
Friedman A, Perrimon N (2006) A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature 444:230–234
Friedman AA, Tucker G, Singh R et al (2011) Proteomic and functional genomic landscape of receptor tyrosine kinase and ras to extracellular signal-regulated kinase signaling. Sci Signal 4:ra10
Ashton-Beaucage D, Udell CM, Gendron P et al (2014) A functional screen reveals an extensive layer of transcriptional and splicing control underlying RAS/MAPK signaling in Drosophila. PLoS Biol 12:e1001809
Friedman A, Perrimon N (2007) Genetic screening for signal transduction in the era of network biology. Cell 128:225–231
Eyre TA, Wright MW, Lush MJ et al (2007) HCOP: a searchable database of human orthology predictions. Brief Bioinform 8:2–5
Hu Y, Flockhart I, Vinayagam A et al (2011) An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics 12:357
Ashton-Beaucage D, Therrien M (2010) The greater RTK/RAS/ERK signalling pathway: how genetics has helped piece together a signalling network. Med Sci (Paris) 26:1067–1073
Acknowledgments
D.A.B. was the recipient of a Cole Foundation studentship. This work was supported by funds from the Canadian Institutes for Health Research (CIHR) to M.T. (MOP-119443).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media New York
About this protocol
Cite this protocol
Ashton-Beaucage, D., Therrien, M. (2017). How Genetics Has Helped Piece Together the MAPK Signaling Pathway. In: Jimenez, G. (eds) ERK Signaling. Methods in Molecular Biology, vol 1487. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6424-6_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-6424-6_1
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-6422-2
Online ISBN: 978-1-4939-6424-6
eBook Packages: Springer Protocols