Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins
Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins
复制标题
DOI：
10.1093/emboj/16.21.6426
复制
发表时间：
1997-11-03
期刊：
影响因子：
11.4
通讯作者：
Cobb, MH
中科院分区：
文献类型：
--
作者：
Frost, JA;Steen, H;Cobb, MH
有丝分裂原通过改变细胞代谢、基因表达和细胞骨架组织的整合信号转导网络促进细胞生长。许多这样的信号通过激活MAP激酶级联传播，部分受上游小GTP结合蛋白的调节。级联之间的相互作用是可疑的，但尚未确定。在这里，我们表明，Rho家族小G蛋白，如Rac 1和Cdc 42 hs，激活JNK/SAPK途径，与Raf-1合作激活ERK途径。这导致三元复合物因子（TCFs）的激活，其通过血清反应元件调节c-fos基因表达。ERK途径激酶的检查表明，MEK 1和Ras都不会与Rho型蛋白协同作用，并且只有MEK 1被完全激活，这表明MEKs是交叉级联调节的焦点。Rho家族蛋白质利用PAK实现这种效果，因为活性PAK 1突变体的表达可以取代Rho家族小G蛋白，并且干扰PAK 1突变体的表达阻断了ERK的Rho型蛋白质刺激。PAK 1磷酸化丝氨酸298上的MEK 1，这是Raf-1与MEK 1在体内结合的重要位点。干扰PAK 1的表达也减少了血清生长因子对TCF功能的刺激，而活性PAK 1的表达增强了EGF刺激的MEK 1活性。这表明MAP激酶途径元素之间的相互作用，以前没有认识到，并提出了一个解释的Raf-1和Rho家族蛋白质的细胞转化的协同作用。
Mitogens promote cell growth through integrated signal transduction networks that alter cellular metabolism, gene expression and cytoskeletal organization. Many such signals are propagated through activation of MAP kinase cascades partly regulated by upstream small GTP-binding proteins. Interactions among cascades are suspected but not defined. Here we show that Rho family small G proteins such as Rac1 and Cdc42hs, which activate the JNK/SAPK pathway, cooperate with Raf-1 to activate the ERK pathway. This causes activation of ternary complex factors (TCFs), which regulate c-fos gene expression through the serum response element. Examination of ERK pathway kinases shows that neither MEK1 nor Ras will synergize with Rho-type proteins, and that only MEK1 is fully activated, indicating that MEKs are a focal point for cross-cascade regulation. Rho family proteins utilize PAKs for this effect, as expression of an active PAK1 mutant can substitute for Rho family small G proteins, and expression of an interfering PAK1 mutant blocks Rho-type protein stimulation of ERKs. PAK1 phosphorylates MEK1 on Ser298, a site important for binding of Raf-1 to MEK1 in vivo. Expression of interfering PAK1 also reduces stimulation of TCF function by serum growth factors, while expression of active PAK1 enhances EGF-stimulated MEK1 activity. This demonstrates interaction among MAP kinase pathway elements not previously recognized and suggests an explanation for the cooperative effect of Raf-1 and Rho family proteins on cellular transformation.