Negative regulation of MAPK pathway

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Homo sapiens
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The duration and extent of activated MAPK signaling is regulated at many levels through mechanisms that include phosphorylation and dephosphorylation, changes to protein interacting partners and subcellular localization (reviewed in Matallanas et al, 2011).

Activated RAF proteins are subject to MAPK-dependent phosphorylation that promotes the subsequent dephosphorylation of the activation loop and NtA region, terminating RAF kinase activity. This dephosphorylation, catalyzed by PP2A and PP5, primes the RAF proteins for PKA or AKT-mediated phosphorylation of residues S259 and S621, restoring the 14-3-3 binding sites and returning the RAF proteins to the inactive state (von Kriegsheim et al, 2006; Dougherty et al, 2005; reviewed in Matallanas et al, 2011). The phosphorylated RAF1 NtA is also subject to additional regulation through binding to the PEBP1 protein, which promotes its dissociation from MAP2K substrates (Shin et al, 2009).

Activated MAPK proteins also phosphorylate T292 of MAP2K1; this phosphorylation limits the activity of MAP2K1, and indirectly affects MAP2K2 activity through by modulating the activity of the MAP2K heterodimer (Catalanotti et al, 2009; reviewed in Matallanas et al, 2011).

Dephosphorylation of MAPKs by the dual specificity MAPK phosphatases (DUSPs) plays a key role in limiting the extent of pathway activation (Owens et al, 2007; reviewed in Roskoski, 2012b). Class I DUSPs are localized in the nucleus and are induced by activation of the MAPK pathway, establishing a negative feedback loop, while class II DUSPs dephosphorylate cytoplasmic MAPKs (reviewed in Rososki, 2012b).
MAPK signaling is also regulated by the RAS GAP-mediated stimulation of intrinsic RAS GTPase activity which returns RAS to the inactive, GDP bound state (reviewed in King et al, 2013).
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
17496916 Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases

Keyse, SM, Owens, DM

Oncogene 2007
19158341 Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway

Fee, F, Shin, SY, McFerran, B, Cho, KH, Kolch, W, Choo, SM, Rath, O

J. Cell. Sci. 2009
16892053 Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5

Grindlay, GJ, Dhillon, AS, Kolch, W, Pitt, A, von Kriegsheim, A

Nat. Cell Biol. 2006
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
23443682 Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis

Lapinski, PE, Lubeck, BA, King, PD

Sci Signal 2013
15664191 Regulation of Raf-1 by direct feedback phosphorylation

Zhou, XZ, Veenstra, TD, Dougherty, MK, Lu, KP, Müller, J, Copeland, TD, Zhou, M, Morrison, DK, Conrads, TP, Ritt, DA

Mol. Cell 2005
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