HCPTPA, a Protein Tyrosine Phosphatase That Regulates Vascular Endothelial Growth Factor Receptor-mediated Signal Transduction and Biological Activity
| Autor: | Sabita Sankar, Liwen Huang, Shu-Mang Feng, Eugene H. Cha, Michael A. Blanar, Christopher D. Kontos, Zhiming Yu, Kevin G. Peters, Charles Lin, Robert L. Van Etten, Alfred D. Schroff, Su-Feng Li |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Vascular Endothelial Growth Factor A
Phosphotyrosine binding Angiogenesis Neovascularization Physiologic Endothelial Growth Factors Protein tyrosine phosphatase Biochemistry Receptor tyrosine kinase Substrate Specificity Two-Hybrid System Techniques Animals Humans Receptors Growth Factor Phosphorylation Molecular Biology Aorta Cells Cultured Lymphokines biology Vascular Endothelial Growth Factors Receptor Protein-Tyrosine Kinases Cell Biology Molecular biology Recombinant Proteins Rats Cell biology Vascular endothelial growth factor B Vascular endothelial growth factor A Receptors Vascular Endothelial Growth Factor cardiovascular system biology.protein Protein Tyrosine Phosphatases Signal transduction Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 274:38183-38188 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.274.53.38183 |
| Popis: | Angiogenesis is a tightly controlled process in which signaling by the receptors for vascular endothelial growth factor (VEGF) plays a key role. In order to define signaling pathways downstream of VEGF receptors (VEGFR), the kinase domain of VEGFR2 (Flk-1) was used as a bait to screen a human fetal heart library in the yeast two-hybrid system. One of the signaling molecules identified in this effort was HCPTPA, a low molecular weight, cytoplasmic protein tyrosine phosphatase. Although HCPTPA possesses no identifiable phosphotyrosine binding domains (i.e. SH2 or phosphotyrosine binding domains), it bound specifically to active, autophosphorylated VEGFR2 but not to a mutated, kinase-inactive VEGFR2. Recombinant VEGFR2 and endogenous VEGFR2 were substrates for recombinant HCPTPA, and HCPTPA was co-expressed with VEGFR2 in endothelial cell lines, suggesting that HCPTPA may be a negative regulator of VEGFR2 signal transduction. To pursue this possibility, an adenovirus directing the expression of HCPTPA was constructed. When used to infect cultured endothelial cells, this adenovirus directed high level expression of HCPTPA that resulted in impairment of VEGF-mediated VEGFR2 autophosphorylation and mitogen-activated protein kinase activation. Adenovirus-mediated overexpression of HCPTPA also inhibited VEGF-induced cellular responses (endothelial cell migration and proliferation) and inhibited angiogenesis in the rat aortic ring assay. Taken together, these findings indicate that HCPTPA may be an important regulator of VEGF-mediated signaling and biological activity. Potential interactions with other signaling pathways and possible therapeutic implications are discussed. |
| Databáze: | OpenAIRE |
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