Type I collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism 1.

During angiogenesis, a combined action between newly secreted extracellular matrix proteins and the repertoire of integrins expressed by endothelial cells contributes in the regulation of their biological functions. Extracellular matrix-engaged integrins influence tyrosine kinase receptors, thus promoting a regulatory cross-talk between adhesive and soluble stimuli. For instance, vitronectin has been ...
reported to positively regulate VEGFR-2. Here, we show that collagen I downregulates VEGF-A-mediated VEGFR-2 activation. This activity requires the tyrosine phosphatase SHP2, which is recruited to the activated VEGFR-2 when cells are plated on collagen I, but not on vitronectin. Constitutive expression of SHP2(C459S) mutant inhibits the negative role of collagen I on VEGFR-2 phosphorylation. VEGFR-2 undergoes internalisation, which is associated with dynamin II phosphorylation. Expression of SHP2(C459S) impairs receptor internalisation suggesting that SHP2-dependent dephosphorylation regulates this process. These findings demonstrate that collagen I in provisional extracellular matrix surrounding nascent capillaries triggers a signaling pathway that negatively regulates angiogenesis.
Mesh Terms:
Collagen Type I, Endothelial Cells, Humans, Intracellular Signaling Peptides and Proteins, Neovascularization, Physiologic, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatases, Signal Transduction, Tyrosine, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Vitronectin
Circ. Res.
Date: Jan. 06, 2006
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