Molecular mechanisms of signal transduction regulating cell proliferation, cell differentiation and cell cycle

MAP在细胞增殖、分化和转化中起着重要的调节作用。我们已经分析了MAP激酶介导的对接相互作用，它可以调节MAP激酶信号转导的特异性和效率，并发现MAP激酶表面存在一条包括CD结构域和ED位点的对接凹槽。ERK蛋白激酶的功能位于受体酪氨酸激酶的下游，对ERK蛋白激酶信号的时空调控对细胞命运的决定至关重要。我们已经证明Sprouty是一种新型的负反馈抑制剂，它调节ERK活性的持续时间和/或幅度，并证明Sef是一种空间调节因子，它特异性地抑制ERK核转位，而不抑制细胞质中的ERK活性。然后，我们分析了ERK介导的基因表达的时间程序，并揭示了持续激活ERK促进G1期进展的分子基础。Polo-like kinase1(Plk1)是一种进化上保守的M期蛋白激酶，参与多种M期事件。我们已经证明，Plk1调节M期进入的主引擎cdc2/cyClinB复合体和cdc2/cyClinB复合体的激活剂cdc25C的核输入。此外，我们的结果还确定了Plk1共同的磷酸化基序，并表明蛋白激酶Myt1是Plk1的底物。

MAP kinase is shown to play an important role in regulation of cell proliferation, cell differentiation, and cell transformation. We have analyzed the MAP kinase-mediated docking interaction that could regulate the specificity and efficiency of the MAP kinase signal transduction, and identified a docking groove on the surface of MAP kinase that includes the CD domain and the ED site. ERK MAP kinase functions downstream of receptor tyrosine kinase, and spatiotemporal control of ERK MAP kinase signaling is crucial for cell fate decision. We have shown that Sprouty is a novel type of negative feedback inhibitor that regulates the duration and/or magnitude of ERK activity, and demonstrated that Sef is a spatial regulator that specifically inhibits ERK nuclear translocation without inhibiting ERK activity in the cytoplasm. We have then analyzed that temporal program of ERK-mediated gene expression, and revealed a molecular basis underlying the mechanism by which sustained ERK activation promotes G1 phase progression. Polo-like kinase 1 (Plk1) is an evolutionarily conserved M phase protein kinase that is involved in a wide variety of M phase events. We have demonstrated that Plk1 regulates nuclear import of both cdc2/cyclinB complex, the master engine of M phase entry, and cdc25C, the activator of cdc2/cyclinB complex. In addition, our results have identified the consensus phosphorylation motif by Plk1, and shown that the protein kinase Myt1 is a substrate of Plk1.