p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner.

p21 激活的激酶 1 (PAK1) 可以非激酶依赖性的方式促进 ERK 的激活。

• 发表时间: Jul 2013 5
• 来源期刊: J Biol Chem
• DOI: 10.1074/jbc.M112.426023
• PMID: 23653349
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Wang Z,Fu M,Wang L,Liu J,Li Y,Brakebusch C,Mei Q

关键词: ERK; MAP Kinases (MAPKs); MEK; PAK; RAF; Rac1; Scaffold Proteins

Mesh: Animals; Enzyme Activation / physiology; HEK293 Cells; HeLa Cells; Humans; MAP Kinase Kinase 1 / genetics metabolism; MAP Kinase Kinase 2 / genetics metabolism; MAP Kinase Signaling System / physiology; Mice; NIH 3T3 Cells; Neuropeptides / genetics metabolism; Phosphorylation / physiology; Proto-Oncogene Proteins B-raf / genetics metabolism; Proto-Oncogene Proteins c-raf / genetics metabolism; p21-Activated Kinases / genetics metabolism; rac GTP-Binding Proteins / genetics metabolism; rac1 GTP-Binding Protein / genetics metabolism

Abstract

PAK1 plays an important role in proliferation and tumorigenesis, at least partially by promoting ERK phosphorylation of C-RAF (Ser-338) or MEK1 (Ser-298). We observed how that overexpression of a kinase-dead mutant form of PAK1 increased phosphorylation of MEK1/2 (Ser-217/Ser-221) and ERK (Thr-202/Tyr-204), although phosphorylation of B-RAF (Ser-445) and C-RAF (Ser-338) remained unchanged. Furthermore, increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1, PAK1, and MEK1 independent of the kinase activity of PAK1. These data suggest that PAK1 can stimulate MEK activity in a kinase-independent manner, probably by serving as a scaffold to facilitate interaction of C-RAF.

摘要

PAK1在增殖和肿瘤发生中起重要作用，至少部分地通过促进C-RAF(Ser-338)或MEK1(Ser-298)的ERK磷酸化。我们观察到PAK1的激酶死亡突变形式的过表达如何增加MEK1/2（Ser-217/Ser-221）和ERK（Thr-202/Tyr-204）的磷酸化，尽管B-RAF（Ser-445）和C-RAF（Ser-338）的磷酸化保持不变。此外，PAK1激活剂Rac1的增加激活诱导Rac1，PAK1和MEK1的三重复合物的形成，而与PAK1的激酶活性无关。这些数据表明PAK1可以以不依赖激酶的方式刺激MEK活性，可能通过充当支架来促进C-RAF的相互作用。