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Published 12 September 2005. doi:10.1083/jcb.200507082
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 6, 993-1004
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Article

 Stable interaction between {alpha}5ß1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1

Ilaria Cascone, Lucia Napione, Fabrizio Maniero, Guido Serini, and Federico Bussolino

Department of Oncological Sciences and Institute for Cancer Research and Treatment, University of Torino, 10060 Candiolo, Italy

Correspondence to Ilaria Cascone: ilaria.cascone{at}curie.fr

During angiogenic remodeling, Ang-1, the ligand of Tie2 tyrosine kinase, is involved in vessel sprouting and stabilization through unclear effects on nascent capillaries and mural cells. In our study, we hypothesized that the Ang-1/Tie2 system could cross-talk with integrins, and be influenced by the dynamic interactions between extracellular matrix and endothelial cells (ECs). Here, we show that {alpha}5ß1 specifically sensitizes and modulates Tie2 receptor activation and signaling, allowing EC survival at low concentrations of Ang-1 and inducing persistent EC motility. Tie2 and {alpha}5ß1 interact constitutively; {alpha}5ß1 binding to fibronectin increases this association, whereas Ang-1 stimulation recruits p85 and FAK to this complex. Furthermore, we demonstrate that Ang-1 is able to mediate selectively {alpha}5ß1 outside-in FAK phosphorylation. Thus, Ang-1 triggers signaling pathways through Tie2 and {alpha}5ß1 receptors that could cross-talk when Tie2/{alpha}5ß1 interaction occurs in ECs plated on fibronectin. By using blocking antibodies, we consistently found that {alpha}5ß1, but not {alpha}vß3 activation, is essential to Ang-1–dependent angiogenesis in vivo.

I. Cascone and L. Napione contributed equally to this work.

I. Cascone's present address is Institut Curie, INSERM U528, rue d'Ulm 26, 75248 Paris Cedex 05, France.

Abbreviations used in this paper: Ab, antibody; anti-CBP, anti-fibronectin cell binding peptide mAb; CAM, chick chorioallantoic membrane; EC, endothelial cell; ECM, extracellular matrix; MTT, [(3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium]; PAE, porcine aortic endothelial; PI3-K, phosphatidylinositol-3-kinase; VEGF, vascular endothelial growth factor. VEGFR, vascular endothelial growth factor receptor.


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