Signals from both integrins and growth factor receptors are required for hematopoietic cell growth, implying that these signals converge at some point(s) to determine key cell cycle regulatory events. Previous work has identified the small GTPase Rho as a component of an integrin signaling pathway, and recent preliminary data show that activation of MAP kinase by growth factors also requires cell adhesion. We propose to investigate how integrin- and growth factor receptor- dependent signals converge by investigating the MAP kinase pathway and downstream events that determine cell cycle progression. The requirement for integrin-mediated cell adhesion in activation of MAP kinase by growth factors will be characterized in more detail, and the point in the MAP kinase pathway at which integrin-mediated signals intersect will be determined. In addition, the mechanisms by which integrin activation of Rho and MAP kinase regulates gene expression from the fos promoter and G1 cyclin levels and activity will be studied. These studies should, therefore, lead to an understanding of how cell adhesion and growth factors combine to regulate cell growth at the level of an early signaling pathway, an early gene expression event, and events late in G1. These issues are fundamental to the regulation of proliferation and other functions inhematopoietic cells and other cell types.
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