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.
Mitola
Stefania
S
Institute for Cancer Research and Treatment, Department of Oncological Sciences, University of Torino, Turin, Italy.
Brenchio
Barbara
B
Piccinini
Marco
M
Tertoolen
Leon
L
Zammataro
Luca
L
Breier
Georg
G
Rinaudo
Maria Teresa
MT
den Hertog
Jeroen
J
Arese
Marco
M
Bussolino
Federico
F
D024042:Collagen Type I / Q000494:pharmacology*; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D019096:Vitronectin / Q000494:pharmacology
D024042:Collagen Type I; D047908:Intracellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D019096:Vitronectin; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases