King A J, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, Marshall M S
Department of Medicine, Indiana University School of Medicine, The Walther Oncology Center, Indianapolis 46202, USA.
Nature. 1998 Nov 12;396(6707):180-3. doi: 10.1038/24184.
The pathway involving the signalling protein p21Ras propagates a range of extracellular signals from receptors on the cell membrane to the cytoplasm and nucleus. The Ras proteins regulate many effectors, including members of the Raf family of protein kinases. Ras-dependent activation of Raf-1 at the plasma membrane involves phosphorylation events, protein-protein interactions and structural changes. Phosphorylation of serine residues 338 or 339 in the catalytic domain of Raf-1 regulates its activation in response to Ras, Src and epidermal growth factor. Here we show that the p21-activated protein kinase Pak3 phosphorylates Raf-1 on serine 338 in vitro and in vivo. The p21-activated protein kinases are regulated by the Rho-family GTPases Rac and Cdc42. Our results indicate that signal transduction through Raf-1 depends on both Ras and the activation of the Pak pathway. As guanine-nucleotide-exchange activity on Rac can be stimulated by a Ras-dependent phosphatidylinositol-3-OH kinase, a mechanism could exist through which one Ras effector pathway can be influenced by another.
涉及信号蛋白p21Ras的信号通路可将一系列细胞外信号从细胞膜上的受体传递至细胞质和细胞核。Ras蛋白调控多种效应器，包括蛋白激酶Raf家族的成员。Ras依赖的Raf-1在质膜上的激活涉及磷酸化事件、蛋白质-蛋白质相互作用和结构变化。Raf-1催化结构域中丝氨酸残基338或339的磷酸化调节其对Ras、Src和表皮生长因子的响应激活。在此我们表明，p21激活的蛋白激酶Pak3在体外和体内均可使Raf-1的丝氨酸338磷酸化。p21激活的蛋白激酶受Rho家族GTP酶Rac和Cdc42的调控。我们的结果表明，通过Raf-1的信号转导既依赖于Ras，也依赖于Pak信号通路的激活。由于Rac上的鸟嘌呤核苷酸交换活性可被Ras依赖的磷脂酰肌醇-3-OH激酶刺激，可能存在一种机制，通过该机制一条Ras效应器通路可受另一条通路的影响。
