Document Detail


Integrin β3 crosstalk with VEGFR accommodating tyrosine phosphorylation as a regulatory switch.
MedLine Citation:
PMID:  22363548     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 β(3) 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 β(3) and VEGFR2. Specifically, the membrane-proximal motif around (801)YLSI in VEGFR2 mediates its binding to non-phosphorylated β(3)CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y(747) phosphorylation of β(3) enhances the above interaction. To demonstrate the importance of β(3) phosphorylation in endothelial cell functions, we synthesized β(3)CT-mimicking Y(747) phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y(747) but not F(747) significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y(747) peptide exhibits inhibitory effect only in WT but not in β(3) integrin knock-out or β(3) integrin knock-in cells expressing β(3) 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.
Authors:
Xiaoxia Z West; Nahum Meller; Nikolay L Malinin; Lalit Deshmukh; Julia Meller; Ganapati H Mahabeleshwar; Malory E Weber; Bethany A Kerr; Olga Vinogradova; Tatiana V Byzova
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-17
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-02-24     Completed Date:  2012-06-29     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e31071     Citation Subset:  IM    
Affiliation:
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Amino Acid Sequence
Animals
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism
Human Umbilical Vein Endothelial Cells / drug effects,  enzymology
Humans
Integrin beta3 / chemistry,  metabolism*
Magnetic Resonance Spectroscopy
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Neovascularization, Physiologic
Peptides / chemistry,  metabolism,  pharmacology
Phosphorylation / drug effects
Phosphotyrosine / metabolism*
Protein Binding / drug effects
Receptor Cross-Talk* / drug effects
Signal Transduction / drug effects
Vascular Endothelial Growth Factor A / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / chemistry,  metabolism*
Grant Support
ID/Acronym/Agency:
R21 HL098777/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Integrin beta3; 0/Peptides; 0/Vascular Endothelial Growth Factor A; 21820-51-9/Phosphotyrosine; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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