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

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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.