Signals emanating from the extracellular matrix have a major influence on cell growth and differentiation. The integrin family of adhesion receptors clearly plays a key role in transducing signals from the matrix to the cell interior. In certain cell types integrin signaling pathways may impinge on control of the cell cycle and cell growth. In other cell types integrin signals may trigger the expression of genes associated with cell differentiation. Thus similar initial signaling events may result in different outcomes depending on the cell context. The interaction of integrins with extracellular matrix ligands can result in the activation of cytoplasmic tyrosine kinases, including pp125FAK, a novel focal adhesion associated kinase. However, little is known about subsequent downstream events in the integrin signaling cascade. We have recently found that integrin ligation can lead to the activation of MAP kinases in fibroblasts. Based on this observation, we hypothesize that integrin-derived signals may impinge on the Ras/ Raf/Mek/MAP kinase cascade also known to be involved in peptide mitogen signaling. Thus, signals from integrins and from mitogenic factors may converge in the regulation of cell cycle traverse and cell growth in fibroblasts.
In Aim I of this proposal, we will test the hypothesis that integrin-mediated signaling shares common elements with receptor tyrosine kinase signal transduction pathways. In these studies in fibroblasts we will: (a) define features of integrin alpha and beta subunits that are critical for signal transduction; (b)determine if Ras and Raf play an important role in integrin signaling; (c) determine if FAK is essential to downstream events in the integrin signaling pathway; (d) explore the role of the cytoskeleton in integrin signaling. These studies should lead to fundamental insights into mechanisms of integrin mediated signal transduction that may be involved in growth regulation. In differentiated monocytic cells, integrin ligation leads to the induction of a number of immediate-early (IE) genes, many of which are regulated by NFk/IkB transcription factors. We have recently shown that tyrosine phosphorylation is required for integrin-mediated gene induction in monocytes, but that pp125FAK is not involved.
In Aim II of this proposal, we will elucidate the integrin signaling pathway leading to activation of IE genes in monocytic cells. This may serve as a model for integrin signaling in other differentiated cell types. In these studies we will: (a) define features of integrin alpha and beta subunits that are critical for IE gene induction; (b) determine if Ras, Raf and MAP kinases play an important role in integrin signaling in monocytic cells; (c) characterize an integrin-responsive tyrosine kinase in monocytic cells that is distinct from FAK. These studies will delineate an important integrin signaling pathway that contributes to cell differentiation.
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