MAPK 通路的负调节
中文名称
通路描述
MAPK 通路的激活程度和范围通过多种机制（包括磷酸化和去磷酸化、蛋白质相互作用伙伴的变化以及亚细胞定位的改变）在多个水平上进行调节（参见 Matallanas 等，2011）。活化的 RAF 蛋白受到 MAPK 依赖性磷酸化，该过程促进激活环和 NtA 区域的去磷酸化，从而终止 RAF 激酶活性。这种去磷酸化由 PP2A 和 PP5 催化，使 RAF 蛋白处于可被 PKA 或 AKT 介导的 S259 和 S621 位点磷酸化的状态，恢复 14-3-3 结合位点，并将 RAF 蛋白恢复到无活性状态（von Kriegsheim 等，2006；Dougherty 等，2005；参见 Matallanas 等，2011）。活化的 MAPK1 NtA 还受到 PEBP1 蛋白的进一步调节，该蛋白促进其与 MAP2K 底物的解离（Shin 等，2009）。活化的 MAPK 蛋白也会磷酸化 MAP2K1 的 T292 位点；这种磷酸化限制了 MAP2K1 的活性，并通过调节 MAP2K 异二聚体的活性间接影响 MAP2K2 的活性（Catalanotti 等，2009；参见 Matallanas 等，2011）。MAPK 的去磷酸化由双特异性 MAPK 磷酸酶（DUSPs）介导，在限制通路激活程度方面起着关键作用（Owens 等，2007；参见 Roskoski，2012b）。I 类 DUSPs 定位于细胞核，并受 MAPK 通路激活诱导，建立负反馈回路，而 II 类 DUSPs 则去磷酸化细胞质 MAPK（参见 Rososki，2012b）。MAPK 信号还受 RAS GAP 介导的内在 RAS GTP 酶活性激活的调节，该过程将 RAS 返回到无活性的 GDP 结合状态（参见 King 等，2013）。
英文描述
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).
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).
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).
所含基因
37 个基因