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J. Cell Biol. 168 (4): 643-653

Copyright © 2005 by the Rockefeller University Press.

Article

Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by ß1 integrins

Sarah M. Short1, Alexandrine Derrien1, Radha P. Narsimhan5, Jack Lawler4, Donald E. Ingber1,3, , and Bruce R. Zetter1,2

1 Vascular Biology Program, Children's Hospital
2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
3 Department of Pathology, Harvard Medical School, Boston, MA 02115
4 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115
5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115

Correspondence to Bruce R. Zetter: bruce.zetter{at}childrens.harvard.edu

Abstract: The anti-angiogenic effect of thrombospondin-1 has been shown to be mediated through binding of the type-1 repeat (TSR) domain to the CD36 transmembrane receptor. We now report that the TSR domain can inhibit VEGF-induced migration in human umbilical vein endothelial cells (HUVEC), cells that lack CD36. Moreover, we identified ß1 integrins as a critical receptor in TSR-mediated inhibition of migration in HUVEC. Using pharmacological inhibitors of downstream VEGF receptor effectors, we found that phosphoinositide 3-kinase (PI3k) was essential for TSR-mediated inhibition of HUVEC migration, but that neither PLC{gamma} nor Akt was necessary for this response. Furthermore, ß1 integrins were critical for TSR-mediated inhibition of microvascular endothelial cells, cells that express CD36. Together, our results indicate that ß1 integrins mediate the anti-migratory effects of TSR through a PI3k-dependent mechanism.

Abbreviations used in this paper: EBM, endothelial basal medium; HMVEC, human microvascular endothelial cells; HSA, horse serum albumin; HUVEC, human umbilical vein endothelial cells; IAP/CD47, integrin-associated protein; PI3k, phosphoinositide 3-kinase; RGD, Arg-Gly-Asp; siRNA, small interfering RNA; TSP1, thrombospondin-1; TSR, type-1 repeat.

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