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(Circulation Research. 2006;98:45.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Type I Collagen Limits VEGFR-2 Signaling by a SHP2 Protein-Tyrosine Phosphatase–Dependent Mechanism 1

Stefania Mitola, Barbara Brenchio, Marco Piccinini, Leon Tertoolen, Luca Zammataro, Georg Breier, Maria Teresa Rinaudo, Jeroen den Hertog, Marco Arese, Federico Bussolino

From the Institute for Cancer Research and Treatment (S.M., B.B., L.Z., M.A., F.B.), Department of Oncological Sciences (S.M., B.B., L.Z., M.A., F.B.), Department of Medicine and Experimental Oncology (M.P., M.T.R.), University of Torino, Torino, Italy; Netherlands Institute for Developmental Biology (L.T., J.d.H.), Utrecht, The Netherlands; Max Planck Institute for Physiological and Clinical Research (G.B.), D-61231 Bad Nauheim, Germany; University Clinic Carl Gustav Carus (G.B.), Dresden, Germany.

Correspondence to Federico Bussolino, MD, IRCC, Strada provinciale 142, Km 3.95. 10060 Candiolo, Italy. E-mail federico.bussolino{at}ircc.it

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.

Key Words: endothelial cell • extracellular matrix • tyrosine kinase receptor • tyrosine phosphatase

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