Integrin alpha(v)beta(3) is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase beta/zeta.
We have previously shown that the angiogenic growth factor pleiotrophin (PTN) induces migration of endothelial cells through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta). In this study, we show that a monoclonal antibody against alpha(nu)beta(3) but not alpha(5)beta(1) integrin abolished PTN-induced human endothelial cell migration in a concentration-dependent manner. Integrin alpha(nu)beta(3) was found to directly interact with PTN in an RGD-independent manner, whereas a synthetic peptide corresponding to the specificity loop of the beta(3) integrin extracellular domain ((177)CYDMKTTC(184)) inhibited PTN-alpha(nu)beta(3) interaction and totally abolished PTN-induced endothelial cell migration. Interestingly, alpha(nu)beta(3) was also found to directly interact with RPTPbeta/zeta, and PTN-induced Y773 phosphorylation of beta(3) integrin was dependent on both RPTPbeta/zeta and the downstream c-src kinase activation. Midkine was found to interact with RPTPbeta/zeta, but not with alpha(nu)beta(3), 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 RPTPbeta/zeta but do not express alpha(nu)beta(3), while it stimulated migration of U87MG cells that express alpha(nu)beta(3) on their cell membrane. Overexpression or down-regulation of beta(3) stimulated or abolished, respectively, the effect of PTN on cell migration. Collectively, these data suggest that alpha(nu)beta(3) is a key molecule that determines the stimulatory or inhibitory effect of PTN on cell migration.
Mikelis
Constantinos
C
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR 26504, Greece.
Sfaelou
Evanthia
E
Koutsioumpa
Marina
M
Kieffer
Nelly
N
Papadimitriou
Evangelia
E
D002352:Carrier Proteins / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D000078792:Midkine; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D016207:Cytokines; D039302:Integrin alphaVbeta3; C066845:pleiotrophin; D000078792:Midkine; D019061:src-Family Kinases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5