Integrin activation is required for platelet aggregation in thrombosis and hemostasis and plays an important role in the migration of endothelial cells and in angiogenesis. Our previous work led to the discovery of an Integrin Activation Complex (IAC) containing Rap-interacting Adaptor Molecule (RIAM), talin, and integrins. To test the hypothesis that the IAC contains a characteristic population of proteins, we will characterize the IAC in detail by establishing its protein composition by use of a novel tandem affinity tag approach to purify unoccupied integrins in complex with RIAM and utilize mass spectrometry to specify the protein cartography (proteome) of these isolated complexes. Bioinformatics will be used to project the identified proteome onto physical, genetic, and pathway protein-protein interaction networks to help select identified IAC components for validation by direct immunoprecipitation and purified protein-protein interactions. To test the hypothesis to that IACs of differing composition exist in specific cellular compartments, we will devise a novel bimolecular fluorescence complementation method to visualize the IAC and relate its position to specific cellular locales e.g. lamellipodium or specific vesicle populations. To test the hypothesi to that components of the IAC have specific roles in the formation or behavior of the IAC and in integrin activation and cell migration, we will examine the effects of elimination of IAC components on the movements of the IAC, integrin activation, cell migration, actin flow, and protrusion morphodynamics. These studies will establish biochemical and cell biological means to characterize and study modular assemblies of proteins that control integrin activation and the integrin-dependent regulation of actin dynamics and cell migration. The work will therefore provide new insights into the mechanisms of integrin activation involved in arterial thrombosis and inflammation. The studies will also contribute insights into mechanisms controlling the migration of vascular cells.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Kindzelski, Andrei L
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Ye, Feng; Yang, Chansik; Kim, Jiyoon et al. (2017) Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains. J Biol Chem 292:9858-9864
Baumer, Yvonne; McCurdy, Sara; Alcala, Martin et al. (2017) CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 256:105-114
Bajaj, Jeevisha; Konuma, Takaaki; Lytle, Nikki K et al. (2016) CD98-Mediated Adhesive Signaling Enables the Establishment and Propagation of Acute Myelogenous Leukemia. Cancer Cell 30:792-805
Gingras, Alexandre R; Puzon-McLaughlin, Wilma; Bobkov, Andrey A et al. (2016) Structural Basis of Dimeric Rasip1 RA Domain Recognition of the Ras Subfamily of GTP-Binding Proteins. Structure 24:2152-2162
de Kreuk, Bart-Jan; Gingras, Alexandre R; Knight, James Dr et al. (2016) Heart of glass anchors Rasip1 at endothelial cell-cell junctions to support vascular integrity. Elife 5:e11394
Schmidt, Thomas; Ye, Feng; Situ, Alan J et al. (2016) A Conserved Ectodomain-Transmembrane Domain Linker Motif Tunes the Allosteric Regulation of Cell Surface Receptors. J Biol Chem 291:17536-46
de la Ballina, Laura R; Cano-Crespo, Sara; González-Muñoz, Elena et al. (2016) Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability. J Biol Chem 291:9700-11
Abplanalp, Wesley T; Conklin, Daniel J; Cantor, Joseph M et al. (2016) Enhanced Integrin ?4?1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes 65:3505-3515
Lagarrigue, Frederic; Kim, Chungho; Ginsberg, Mark H (2016) The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood 128:479-87
Schmidt, Thomas; Suk, Jae-Eun; Ye, Feng et al. (2015) Annular anionic lipids stabilize the integrin ?IIb?3 transmembrane complex. J Biol Chem 290:8283-93

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