The extracellular matrix (ECM) provides cues to cells and thus serves as a framework for cell proliferation, migration, adhesion, and differentiation. Cell responses to changes in matrix composition and structure are interpreted through interactions with integrins and other receptors for matrix proteins. Cytoskeletal reorganization, changes in cell morphology, activation of signal transduction cascades, modulation of gene expression patterns, and progression through the cell cycle represent some of the cellular responses to matrix signals. The overall goal of this new proposal is to provide insights into the control of cell phenotype by ECM interactions with integrin receptors. Fibronectin (FN), an essential ECM component, interacts with cells from within a 3-dimensional fibrillar matrix. The structure of FN matrix fibrils can be varied by cell assembly of different recombinant native and mutant FNs. The principal investigator has found that structurally distinct FN matrices have different effects on cell growth rates and activation of focal adhesion kinase. These differential effects are ablated by inhibition of FN fibril formation. The mechanisms by which matrix FN modulates cell function will be investigated using cell culture systems combined with microscopic, biochemical, and molecular approaches.
Aim 1 is to analyze the role of focal adhesion components, cell shape, and other cell surface receptors in the growth response to FN matrix structure.
Aim 2 is to examine the contributions of downstream signaling pathways involving MAP kinase and PI3-kinase to cell growth and regulation of FN assembly. Integrin cytoplasmic domains are essential for the transmission of signals from the matrix through integrins to intracellular compartments. To dissect cytoplasmic domain function, the PI has developed an in vivo, Caenorhabditis elegans model system. Dominant negative phenotypes are generated in transgenic nematodes expressing chimeric proteins containing integrin b tails.
Aim 3 is to characterize the phenotypes caused by intact and mutant b tails in such transgenic nematodes.
Aim 4 is to to screen mutant transgenic nematode lines and thus identify genes that particpate in integrin function.
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