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J. Biol. Chem., Vol. 278, Issue 21, 19272-19279, May 23, 2003

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Thymidine Phosphorylase and 2-Deoxyribose Stimulate Human Endothelial Cell Migration by Specific Activation of the Integrins ₅₁ and _V3^*

Kylie A. Hotchkiss , Anthony W. Ashton  and Edward L. Schwartz  ¶

From the Department of Oncology, Albert Einstein College of Medicine, Bronx, New York 10467, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York 10467

Thymidine phosphorylase is an angiogenic factor that is frequently overexpressed in solid tumors, in rheumatoid arthritis, and in response to inflammatory cytokines. Our previous studies showed that cells expressing thymidine phosphorylase stimulated endothelial cell migration in vitro. This was a consequence of the intracellular metabolism of thymidine by thymidine phosphorylase and subsequent extracellular release of 2-deoxyribose. The mechanisms by which 2-deoxyribose might mediate thymidine phosphorylase-induced cell migration in vitro, however, are obscure. Here we show that both thymidine phosphorylase and 2-deoxyribose stimulated the formation of focal adhesions and the tyrosine 397 phosphorylation of focal adhesion kinase in human umbilical vein endothelial cells. Although similar actions occurred upon treatment with the angiogenic factor vascular endothelial growth factor (VEGF), thymidine phosphorylase differed from VEGF in that its effect on endothelial cell migration was blocked by antibodies to either integrin ₅₁ or _v3, whereas VEGF-induced endothelial cell migration was only blocked by the _v3 antibody. Further, thymidine phosphorylase and 2-deoxyribose, but not VEGF, increased the association of both focal adhesion kinase and the focal adhesion-associated protein vinculin with integrin ₅₁ and, in intact cells, increased the co-localization of focal adhesion kinase with ₅₁. Thymidine phosphorylase and 2-deoxyribose-induced focal adhesion kinase phosphorylation was blocked by the antibodies to ₅₁ and _v3, directly linking the migration and signaling components of thymidine phosphorylase and 2-deoxyribose action. Cell surface expression of ₅₁ was also increased by thymidine phosphorylase and 2-deoxyribose. These experiments are the first to demonstrate a direct effect of thymidine phosphorylase and 2-deoxyribose on signaling pathways associated with endothelial cell migration.

Received for publication, December 12, 2002 , and in revised form, February 6, 2003.

^¶ To whom correspondence should be addressed: Dept. of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467. Tel.: 718-920-4015; Fax: 718-882-4464; E-mail: eschwart{at}aecom.yu.edu.

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