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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
23
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pubmed:dateCreated |
2009-12-7
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Heparan Sulfate Proteoglycans,
http://linkedlifedata.com/resource/pubmed/chemical/Integrin alpha1,
http://linkedlifedata.com/resource/pubmed/chemical/Integrin alpha2beta1,
http://linkedlifedata.com/resource/pubmed/chemical/PTPN6 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/Ptpn6 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/endorepellin protein, human
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1528-0020
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
26
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pubmed:volume |
114
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4897-906
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pubmed:dateRevised |
2011-3-3
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pubmed:meshHeading |
pubmed-meshheading:19789387-Animals,
pubmed-meshheading:19789387-Carcinoma, Lewis Lung,
pubmed-meshheading:19789387-Cell Adhesion,
pubmed-meshheading:19789387-Endothelium, Vascular,
pubmed-meshheading:19789387-Heparan Sulfate Proteoglycans,
pubmed-meshheading:19789387-Humans,
pubmed-meshheading:19789387-Integrin alpha1,
pubmed-meshheading:19789387-Integrin alpha2beta1,
pubmed-meshheading:19789387-Mice,
pubmed-meshheading:19789387-Mice, Inbred C57BL,
pubmed-meshheading:19789387-Mice, Knockout,
pubmed-meshheading:19789387-Neovascularization, Pathologic,
pubmed-meshheading:19789387-Neovascularization, Physiologic,
pubmed-meshheading:19789387-Peptide Fragments,
pubmed-meshheading:19789387-Phosphorylation,
pubmed-meshheading:19789387-Phosphotyrosine,
pubmed-meshheading:19789387-Protein Interaction Mapping,
pubmed-meshheading:19789387-Protein Processing, Post-Translational,
pubmed-meshheading:19789387-Protein Structure, Tertiary,
pubmed-meshheading:19789387-Protein Tyrosine Phosphatase, Non-Receptor Type 6,
pubmed-meshheading:19789387-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:19789387-Recombinant Fusion Proteins,
pubmed-meshheading:19789387-Xenograft Model Antitumor Assays
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pubmed:year |
2009
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pubmed:articleTitle |
Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity.
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pubmed:affiliation |
Department of Pathology, Anatomy, and Cell Biology, and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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