Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity.

Nyström A, Shaik ZP, Gullberg D, Krieg T, Eckes B, Zent R, Pozzi A, Iozzo RV
Blood. 2009 114 (23): 4897-906

PMID: 19789387 · PMCID: PMC2786295 · DOI:10.1182/blood-2009-02-207134

Endorepellin, the C-terminal domain of perlecan, is a powerful angiogenesis inhibitor. To dissect the mechanism of endorepellin-mediated endothelial silencing, we used an antibody array against multiple tyrosine kinase receptors. Endorepellin caused a widespread reduction in phosphorylation of key receptors involved in angiogenesis and a concurrent increase in phosphatase activity in endothelial cells and tumor xenografts. These effects were efficiently hampered by function-blocking antibodies against integrin alpha2beta1, the functional endorepellin receptor. The Src homology-2 protein phosphatase-1 (SHP-1) coprecipitated with integrin alpha2 and was phosphorylated in a dynamic fashion after endorepellin stimulation. Genetic evidence was provided by lack of an endorepellin-evoked phosphatase response in microvascular endothelial cells derived from integrin alpha2beta1(-/-) mice and by response to endorepellin in cells genetically engineered to express the alpha2beta1 integrin, but not in cells either lacking this receptor or expressing a chimera harboring the integrin alpha2 ectodomain fused to the alpha1 intracellular domain. siRNA-mediated knockdown of integrin alpha2 caused a dose-dependent reduction of SHP-1. Finally, the levels of SHP-1 and its enzymatic activity were substantially reduced in multiple organs from alpha2beta1(-/-) mice. Our results show that SHP-1 is an essential mediator of endorepellin activity and discover a novel functional interaction between the integrin alpha2 subunit and SHP-1.

MeSH Terms (23)

Animals Carcinoma, Lewis Lung Cell Adhesion Endothelium, Vascular Heparan Sulfate Proteoglycans Humans Integrin alpha1 Integrin alpha2beta1 Mice Mice, Inbred C57BL Mice, Knockout Neovascularization, Pathologic Neovascularization, Physiologic Peptide Fragments Phosphorylation Phosphotyrosine Protein Interaction Mapping Protein Processing, Post-Translational Protein Structure, Tertiary Protein Tyrosine Phosphatase, Non-Receptor Type 6 Receptor Protein-Tyrosine Kinases Recombinant Fusion Proteins Xenograft Model Antitumor Assays

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