MAP2Ks and MAPKs bind to the activated RAF complex

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Homo sapiens
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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
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