A Peptide Corresponding to the C-terminal Region of Pleiotrophin Inhibits Angiogenesis In Vivo and In Vitro

作者：Mikelis Constantinos; Lamprou Margarita; Koutsioumpa Marina; Koutsioubas Alexandros G; Spyranti Zinovia; Zompra Aikaterini A; Spiliopoulos Nikolaos; Vradis Alexandros A; Katsoris Panagiotis; Spyroulias Georgios A; Cordopatis Paul; Courty Jose; Papadimitriou Evangelia^*

来源：Journal of Cellular Biochemistry, 2011, 112(6): 1532-1543.

DOI：10.1002/jcb.23066

• INTEGRIN
• RECEPTOR PROTEIN TYROSINE PHOSPHATASE
• ENDOTHELIAL CELLS
• MIGRATION
• HEPARIN AFFIN REGULATORY PEPTIDE
• NMR
• SOLUTION STRUCTURE

Pleiotrophin (PTN) is a heparin-binding growth factor that plays a significant role in tumor growth and angiogenesis. We have previously shown that in order for PTN to induce migration of endothelial cells, binding to both alpha(nu)beta(3) integrin and its receptor protein tyrosine phosphatase beta/zeta (RPTP beta/zeta) is required. In the present study we show that a synthetic peptide corresponding to the last 25 amino acids of the C-terminal region of PTN (PTN(112-136)) inhibited angiogenesis in the in vivo chicken embryo chorioallantoic membrane (CAM) assay and PTN-induced migration and tube formation of human endothelial cells in vitro. PTN(112-136) inhibited binding of PTN to alpha(nu)beta(3) integrin, and as shown by surface plasmon resonance (SPR) measurements, specifically interacted with the specificity loop of the extracellular domain of beta(3). Moreover, it abolished PTN-induced FAK Y397 phosphorylation, similarly to the effect of a neutralizing alpha(nu)beta(3)-selective antibody. PTN(112-136) did not affect binding of PTN to RPTP beta/zeta in endothelial cells and induced beta(3) Y773 phosphorylation and ERK1/2 activation to a similar extent with PTN. This effect was inhibited by down-regulation of RPTP beta/zeta by siRNA or by c-src inhibition, suggesting that PTN(112-136) may interact with RPTP beta/zeta. NMR spectroscopy studies showed that PTN(112-136) was characterized by conformational flexibility and absence of any element of secondary structure at room temperature, although the biologically active peptide segment 123-132 may adopt a defined structure at lower temperature. Collectively, our data suggest that although PTN(112-136) induces some of the signaling pathways triggered by PTN, it inhibits PTN-induced angiogenic activities through inhibition of PTN binding to alpha(nu)beta(3) integrin. J. Cell. Biochem. 112: 1532-1543, 2011.

• 出版日期2011-6