摘要：

INTRODUCTIONMAPK-signaling cascades provide an important mechanism to connect the activation of stress responsive proteins to critical regulatory targets within cells, and the dysregulation of MAPK-signaling networks has been linked to the pathogenesis of several disease states, including cancer, diabetes and ischemic injury. Studies designed to illuminate the molecular mechanisms of MAPK-signaling indicate that the propagation and amplification of signals results from a series of phosphorylation dependent reactions, in which the activation of an up-stream kinase leads to the sequential phosphorylation and activation of a series of down-stream kinases. In mammals the major MAP signaling cascades consists of a three-tier network of protein kinases; the MAP-kinase-kinase-kinases (MAPKKKs), the MAP-kinase-kinases (MAPKKs, also referred to as MEKs) and the MAP-kinases (MAPKs). MAPKKKs are ser/thr kinases that receive signals from activated receptors on the cell surface or through interactions with other proteins (e.g. GTP-binding proteins, thioredoxin-1). MAPKKKs act by phosphorylating down-stream substrate proteins, principally MAPKKs. Once phosphorylated, MAPKKs act as "dual-specificity" kinases that phosphorylate ser/thr and tyr residues of MAPKs, thereby stimulating the kinase activity of MAPKs.In humans there are four major families of MAPKs, the extracellular signal- regulated protein kinases (ERK1/2), the c-Jun N-terminal kinases / stress activated protein kinases (JNK1/2/3), the p38 family of kinases (p38α/β/γ/δ) and ERK5 (1). The ERKs are generally responsive to growth factors, and contribute to proliferation, development, differentiation and cell survival. Both the JNKs and the p38s are activated

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