Negative regulation of MAPK pathway

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). <br><br>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). <br><br>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).<br><br>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).<br>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).

MAPK信号通路的激活持续时间与范围在多个层面上受到调控，这些调控机制包括磷酸化与去磷酸化、蛋白质相互作用伙伴的改变以及亚细胞定位（Matallanas 等人，2011年综述）。激活的RAF蛋白受到MAPK依赖的磷酸化作用，该作用促进激活环和NtA区域的后续去磷酸化，从而终止RAF激酶活性。这种去磷酸化，由PP2A和PP5催化，为RAF蛋白的PKA或AKT介导的S259和S621残基磷酸化做准备，恢复14-3-3结合位点，并将RAF蛋白返回至非活性状态（von Kriegsheim 等人，2006年；Dougherty 等人，2005年；Matallanas 等人，2011年综述）。磷酸化的RAF1 NtA还通过结合PEBP1蛋白受到额外的调控，这促进了其从MAP2K底物中解离（Shin 等人，2009年）。激活的MAPK蛋白还磷酸化MAP2K1的T292位点；这种磷酸化限制了MAP2K1的活性，并通过调节MAP2K异源二聚体的活性间接影响MAP2K2的活性（Catalanotti 等人，2009年；Matallanas 等人，2011年综述）。MAPKs的去磷酸化由双特异性MAPK磷酸酶（DUSPs）介导，在限制通路激活范围中发挥着关键作用（Owens 等人，2007年；Roskoski，2012b年综述）。I类DUSPs定位于细胞核中，并由MAPK通路的激活诱导，从而建立负反馈回路，而II类DUSPs去磷酸化细胞质中的MAPK（Rososki，2012b年综述）。MAPK信号通路还受到RAS GAP介导的内在RAS GTPase活性刺激的调控，这使RAS返回至非活性、GDP结合状态（King 等人，2013年综述）。