Reactome | MAP2Ks and MAPKs bind to the activated RAF complex

MAP2Ks and MAPKs bind to the activated RAF complex

Stable Identifier

R-HSA-5672972

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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MAP2Ks and MAPKs bind to the activated RAF complex

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RAF kinases have restricted substrate specificity and have as their primary substrates the two MAP2K proteins MAP2K1 and MAP2K2 (also known as MEK1 and 2). MAP2K1 knockout is embryonic lethal in mice, while MAP2K2 knockouts have no apparent abnormalities, suggesting that MAP2K1 can compensate for MAP2K2 in vivo (Giroux et al, 1999; Belanger et al, 2003). MAP2K proteins exist as stable homo- and heterodimers independent of growth factor stimulation and are generally recruited to activated RAF proteins in conjunction with a scaffolding protein and the MAP2K substrates, MAPK1 and 3 (also known as ERK1 and 2) (Ohren et al, 2004; Catalanotti et al, 2009; Catling et al, 1995; reviewed in Matallanas et al, 2011; Roskoski et al, 2012a; Roskoski et al, 2012b).

Scaffolding proteins promote signaling by providing a docking platform that colocalizes components of the signaling cascade, and provide specificity by controlling the spatial and temporal regulation of the pathway (reviewed in Brown and Sacks, 2009; Matallanas et al, 2011). KSR1 and 2, CNKSR1 and 2, IQGAP1 and the beta arrestins are among the known MAPK scaffold proteins that act at the plasma membrane upon MAPK pathway activation; in addition, paxillin localizes MAPK pathway components to focal adhesion sites in the plasma membrane (Roy et al, 2005; Ren et al, 2007; DeFea et al, 2000; Togho et al, 2003; Ishibe et al, 2003; reviewed in Claperon and Therrien, 2007; Brown and Sacks, 2009; Matallanas et al, 2011). Although this reaction depicts these scaffolding proteins acting equivalently, the details of how they promote pathway activation vary. For instance, KSR1 and 2 are constitutively bound to MAP2K dimers but recruit MAPKs only upon pathway stimulation, while IQGAP1 associates constitutively with both MAP2K and MAPK proteins in unstimulated cells and shows increased interaction with MAP2K1 upon pathway activation by EGF (Stewart et al, 1999; Cacace et al, 2000; Muller et al, 2000; Roy et al, 2004; Roy et al, 2005; reviewed in Brown and Sacks, 2009). Scaffolding complexes may be particularly important for the phosphorylation of cytosolic MAPK targets (reviewed in Casar et al, 2009).

Literature References

PubMed ID	Title	Journal	Year
21779496	Raf family kinases: old dogs have learned new tricks Romano, D, Matallanas, D, Rauch, J, Zebisch, A, Birtwistle, M, Kolch, W, von Kriegsheim, A	Genes Cancer	2011
22569528	ERK1/2 MAP kinases: structure, function, and regulation Roskoski, R Jr	Pharmacol. Res.	2012
10725339	beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2 Mullins, RD, Zalevsky, J, Bunnett, NW, DeFea, KA, Déry, O, Thoma, MS	J. Cell Biol.	2000
12473660	The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation Oakley, RH, Caron, MG, Luttrell, LM, Gesty-Palmer, D, Pierce, KL, Laporte, S, Lefkowitz, RJ, Choy, EW, Tohgo, A	J. Biol. Chem.	2003
9858547	Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression Rubin, GM, Copeland, T, Cacace, AM, Morrison, DK, Mathes, K, Michaud, NR, Therrien, M	Mol Cell Biol	1999
16135787	IQGAP1 is a scaffold for mitogen-activated protein kinase signaling Roy, M, Sacks, DB, Li, Z	Mol. Cell. Biol.	2005
17496912	KSR and CNK: two scaffolds regulating RAS-mediated RAF activation Claperon, A, Therrien, M	Oncogene	2007
17563371	IQGAP1 modulates activation of B-Raf Ren, JG, Sacks, DB, Li, Z	Proc. Natl. Acad. Sci. U.S.A.	2007
10209122	Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta Charron, J, Rousseau, S, Bernard, D, Aubry, S, Landry, J, Huot, J, Giroux, S, Cardin-Girard, JF, Jeannotte, L, Larouche, L, Tremblay, M	Curr. Biol.	1999
14970219	IQGAP1 binds ERK2 and modulates its activity Roy, M, Sacks, DB, Li, Z	J. Biol. Chem.	2004
10409742	Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization Stewart, S, Guan, KL, Lee, J, Zhang, Y, Han, M, Sundaram, M	Mol. Cell. Biol.	1999
12832465	Mek2 is dispensable for mouse growth and development Hugo, P, Tremblay, M, Roy, S, Erikson, R, Steff, AM, Brott, B, Charron, J, Bélanger, LF, Mourad, W	Mol. Cell. Biol.	2003
7565670	A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Reddy, GR, Weber, MJ, Schaeffer, HJ, Reuter, CW, Catling, AD	Mol Cell Biol	1995
15543157	Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition Flamme, C, Whitehead, C, Barrett, S, Mueller, WT, Spessard, C, Pavlovsky, A, Warmus, J, Banotai, C, Delaney, A, Tecle, H, Leung, IK, Dudley, DT, Yan, C, Kaufman, M, Ohren, JF, Omer, C, Kuffa, P, Hasemann, CA, Sebolt-Leopold, J, McConnell, P, Zhang, E, Chen, H	Nat. Struct. Mol. Biol.	2004
10891492	Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling Muller, J, McGill, CB, Lyons, WE, Cacace, AM, Morrison, DK	Mol Cell Biol	2000
19219045	A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal Jesenberger, V, de Matos Simoes, R, Galabova-Kovacs, G, Baccarini, M, Reyes, G, Carugo, O, Catalanotti, F	Nat. Struct. Mol. Biol.	2009
14636584	Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis Joly, D, Zhu, X, Cantley, LG, Ishibe, S	Mol. Cell	2003
19091303	Protein scaffolds in MAP kinase signalling Brown, MD, Sacks, DB	Cell. Signal.	2009
19279408	ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task Crespo, P, Pinto, A, Casar, B	Cell Cycle	2009
22177953	MEK1/2 dual-specificity protein kinases: structure and regulation Roskoski, R Jr	Biochem. Biophys. Res. Commun.	2012