Our overall goal is to understand at the molecular level how integrins work. This includes detailing how cells regulate the function of integrins at the cell surface, uncovering downstream effectors of integrin ligand binding and understanding how integrin heterodimers change conformation upon ligand binding or activation. Integrins are involved in many developmental processes and also function in numerous fully differentiated cells. With respect to known pathological conditions, integrins are essential for blood clotting (and thrombosis), for proper function of the immune system, for the control of proliferation and, when that control fails, in the metastasis of tumors. The PS integrins of Drosophila are very similar to vertebrate integrins, and provide a unique opportunity to examine integrin function in situ. We will pursue lines of investigation that have grown out of recent genetic screens, and which promise to uncover new molecular properties of integrin function. Specifically, we propose to: 1) Determine the mechanistic connections between DIM-7 and integrins. A suppressor screen in flies has identified a functional connection between integrins and DIM-7, a beta importin that is responsible for nuclear import of activated ERK. We will do experiments in both tissue culture cells and flies designed to reveal the molecular nature of this functional interaction. 2) Identify additional suppressors of Blistermaker, a phenotype that results from inappropriate integrin function. The screen that identified the connection between integrins and DIM-7 was biased toward third chromosome mutations. We will conduct similar screens for the other chromosomes, to identify additional components of the integrin regulatory process. 3) Determine requirements for the betaPS PSI domain and serine linker motif. We have preliminary genetic evidence that the N-terminal PSI domain of betaPS subunits is involved in interprotein interactions. We will examine this hypothesis directly, as well as the supposition that an unusual linker motif of betaPS provides an extended tether for the PSI domain.
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