Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells. Blood 2013 Sep 05;122(10):1822-32
Date
07/31/2013Pubmed ID
23896411Pubmed Central ID
PMC3765061DOI
10.1182/blood-2013-01-482315Scopus ID
2-s2.0-84886448895 (requires institutional sign-in at Scopus site) 114 CitationsAbstract
Thrombospondin-1 (TSP-1) inhibits growth factor signaling at the receptor level in microvascular endothelial cells (MVEC), and CD36 has been suggested to be involved in this inhibition, but the mechanisms are not known. We hypothesized that CD36-TSP-1 interaction recruits Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 to the vascular endothelial growth factor receptor 2 (VEGFR2) signaling complex and attenuates vascular endothelial growth factor (VEGF) signaling. Western blots of anti-CD36 and anti-VEGFR2 immunoprecipitates from VEGF-treated MVEC showed that exposure of the cells to a recombinant protein containing the CD36 binding domain of thrombospondin-1 (known as the TSR domain) induced association of SHP-1 with the VEGFR2/CD36 signaling complex and thereby suppressed VEGFR2 phosphorylation. SHP-1 phosphatase activity was increased in immunoprecipitated VEGFR2 complexes from TSR-treated cells. Silencing CD36 expression in MVEC by small interfering RNA (siRNA) or genetic deletion of cd36 in mice showed that TSR-induced SHP-1/VEGFR2 complex formation required CD36 in vitro and in vivo. Silencing SHP-1 expression in MVEC by siRNA abrogated TSR-mediated inhibition of VEGFR2 phosphorylation as well as TSR-mediated inhibition of VEGF-induced endothelial cell migration and tube formation. These studies reveal a SHP-1-mediated antiangiogenic pathway induced by CD36-TSP-1 interaction that inhibits VEGFR2 signaling and they provide a novel target to modulate angiogenesis therapeutically.
Author List
Chu LY, Ramakrishnan DP, Silverstein RLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD36 Antigens
Cell Movement
Endothelial Cells
Gene Deletion
Mice
Mice, Inbred C57BL
Microvessels
Models, Biological
Neovascularization, Physiologic
Phosphorylation
Protein Binding
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Signal Transduction
Thrombospondin 1
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
