FASEB J. Avanti Polar Lipids
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Published as doi: 10.1096/fj.08-117564.
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(The FASEB Journal. 2009;23:1459-1469.)
© 2009 FASEB

Integrin {alpha}{nu}β3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase β/{zeta}

Constantinos Mikelis*, Evanthia Sfaelou*, Marina Koutsioumpa*, Nelly Kieffer{dagger} and Evangelia Papadimitriou*,1

* Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece; and

{dagger} Sino-French Research Center for Life Sciences and Genomics, CNRS/LIA124, Rui Jin Hospital, Jiao Tong University Medical School, Shanghai, China

1 Correspondence: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR 26504 Greece. E-mail: epapad{at}upatras.gr

We have previously shown that the angiogenic growth factor pleiotrophin (PTN) induces migration of endothelial cells through binding to its receptor protein tyrosine phosphatase β/{zeta} (RPTPβ/{zeta}). In this study, we show that a monoclonal antibody against {alpha}{nu}β3 but not {alpha}5β1 integrin abolished PTN-induced human endothelial cell migration in a concentration-dependent manner. Integrin {alpha}{nu}β3 was found to directly interact with PTN in an RGD-independent manner, whereas a synthetic peptide corresponding to the specificity loop of the β3 integrin extracellular domain (177CYDMKTTC184) inhibited PTN-{alpha}{nu}β3 interaction and totally abolished PTN-induced endothelial cell migration. Interestingly, {alpha}{nu}β3 was also found to directly interact with RPTPβ/{zeta}, and PTN-induced Y773 phosphorylation of β3 integrin was dependent on both RPTPβ/{zeta} and the downstream c-src kinase activation. Midkine was found to interact with RPTPβ/{zeta}, but not with {alpha}{nu}β3, and caused a small but statistically significant decrease in cell migration. In the same line, PTN decreased migration of different glioma cell lines that express RPTPβ/{zeta} but do not express {alpha}{nu}β3, while it stimulated migration of U87MG cells that express {alpha}{nu}β3 on their cell membrane. Overexpression or down-regulation of β3 stimulated or abolished, respectively, the effect of PTN on cell migration. Collectively, these data suggest that {alpha}{nu}β3 is a key molecule that determines the stimulatory or inhibitory effect of PTN on cell migration.—Mikelis, C., Sfaelou, E., Koutsioumpa, M., Kieffer, N., Papadimitriou, E. Integrin {alpha}{nu}β3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase β/{zeta}.


Key Words: heparin affin regulatory peptide • heparin-binding growth associated molecule • angiogenesis • tumor growth • glioma






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