%0 Journal Article %T Integrin ¦Â3 Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch %A Xiaoxia Z. West %A Nahum Meller %A Nikolay L. Malinin %A Lalit Deshmukh %A Julia Meller %A Ganapati H. Mahabeleshwar %A Malory E. Weber %A Bethany A. Kerr %A Olga Vinogradova %A Tatiana V. Byzova %J PLOS ONE %D 2012 %I Public Library of Science (PLoS) %R 10.1371/journal.pone.0031071 %X Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between ¦Â3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of ¦Â3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated ¦Â3CT, accommodating an ¦Á-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of ¦Â3 enhances the above interaction. To demonstrate the importance of ¦Â3 phosphorylation in endothelial cell functions, we synthesized ¦Â3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in ¦Â3 integrin knock-out or ¦Â3 integrin knock-in cells expressing ¦Â3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2. %U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031071