ERK通路.doc

ERK通路Ras/Raf/MEK/ERK途径是最重要的信号转导途径之一，不仅因为它涉及到调节细胞的多种生理功能，还有它在多种疾病的发病机制及病理生理过程中发挥着重要的作用，甚至在我们的行为反应和认知方面如学习、记忆等都起着关键的作用 。因此了解该信号转导过程中上游蛋白和各种激酶的激活机制，才能了解生命活动中的一些基本的生理机制和过程，才能寻找针对性的治疗措施。尽管对于该途径中的一些细节问题如Raf在细胞膜上的具体激活机制及自身反馈机制等仍不明了，但目前已有人开始通过抑制该途径上的一些蛋白质或激酶活性来找到治疗疾病的药物及方法。相信在今后的几年中，对ERK通路在体内的作用机制将会阐明得更清楚，从而在疾病的预防和治疗过程中发挥更大的作用。The organisation and function of the RasRafMEKERK pathway. This animation was created in collaboration with the authors by the editorial team of Expert Reviews in Molecular Medicine, and is based on the model presented in Figure 2 (fig002wkg). It summarises the current consensus of the organisation and function of the RasRafMEKERK pathway using epidermal growth factor (EGF) as a paradigm. The binding of EGF induces receptor dimerisation and autophosphorylation (P) on tyrosine residues. These phosphotyrosines function as docking sites for signalling molecules including the Grb2SOS complex, which activates the small G-protein Ras by stimulating the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). This exchange elicits a conformational change in Ras, enabling it to bind to Raf-1 and recruit it from the cytosol to the cell membrane, where Raf-1 activation takes place. Raf-1 activation is a multi-step process that involves the dephosphorylation of inhibitory sites by protein phosphatase 2A (PP2A) as well as the phosphorylation of activating sites by PAK (p21rac/cdc42-activated kinase), Src-family and yet unknown kinases. Activated Raf-1 phosphorylates and activates MEK (MAPK/ERK kinase), which in turn phosphorylates and activates extracellular-signal-regulated kinase (ERK). The interaction between Raf-1 and MEK can be disrupted by RKIP (Raf kinase inhibitor protein; not shown). The whole three-tiered kinase cascade is scaffolded by KSR (kinase suppressor of Ras). Activated ERK has many substrates in the cytosol e.g. cytoskeletal proteins, phospholipase A2, and signalling proteins including tyrosine kinase receptors, oestrogen receptors, SOS, signal transducer and activator of transcription proteins (STATs) and others (Refs 10, 11). ERK can also enter the nucleus to control gene expression by phosphorylating transcription factors such as Elk-1 and other Ets-family proteins. Grb2, growth-factor-receptor-binding protein 2; SOS, son of sevenless; SRF, serum response factor.1.Ras-Raf-MEK-ERK信号通路概览This figure shows the general signaling events involving the Ras RafMEKERK pathway after receptor binding. Shc, Cbl, and Grb representadaptor molecules; SOS is a GTP exhange factor. Receptor engagement results in the recruitment of adaptor molecules and activation of the GTP exchange factor, which in turn activates Ras, resulting in the sequential activation of the Raf, MEK, and ERK kinases. Additional regulation of the pathway is provided by several Y kinases (JAK and Src family of Y kinases), as well as S/T kinases (PKC, KSR, and PKA). The activation of the signaling pathway results in phosphorylation of several enzymes, as well as transcription factors. AC, adenylcyclase; cPKC, conventional PKC; DAG, diacylglycerol; ER, endoplasmic reticulum; ERF, transcription factor member of the Ets family; Gp, G-protein; nPKC, novel PKC; PLP, phospholipase P; SM, sphingomyelin; Smase, sphingomyelinase. 2.Ras-Raf-MEK-ERK信号通路抗凋亡的作用.This figure displays possible points of interaction among the Ras-Raf-MEK-ERK pathway and apoptosis.The activation of caspases results in the cleavage of proteins involved in cell survival, such as Raf-1, Cbl, MEKK1, Pak, FAK, GAP, and Akt, as well as nucleases, which results in DNA cleavage. TF, transcription factor 3.Ras-Raf-MEK-ERK信号通路和细胞周期调控元件的相互作用.The Ras-Raf-MEK-ERK pathway activation results in the activation of transcription factors that induce the transcription