The P2Y2 nucleotide receptor interacts with αv integrins to activate Go and induce cell migration

Sriparna Bagchi, Zhongji Liao, Fernando A. Gonzalez, Nataliya E. Chorna, Cheikh I. Seye, Gary A. Weisman, Laurie Erb

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Extracellular ATP and UTP induce chemotaxis, or directed cell migration, by stimulating the G protein-coupled P2Y2 nucleotide receptor (P2Y 2R). Previously, we found that an arginine-glycine-aspartic acid (RGD) integrin binding domain in the P2Y2R enables this receptor to interact selectively with αvβ3 and αvβ5 integrins, an interaction that is prevented by mutation of the RGD sequence to arginine-glycine-glutamic acid (RGE) (Erb, L., Liu, J., Ockerhausen, J., Kong, Q., Garrad, R. C., Griffin, K., Neal, C., Krugh, B., Santiago-Perez, L. I., Gonzalez, F. A., Gresham, H. D., Turner, J. T., and Weisman, G. A. (2001) J. Cell Biol. 153, 491-501). This RGD domain also was found to be necessary for coupling the P2Y2R to GO- but not Gq-mediated intracellular calcium mobilization, leading us to investigate the role of P2Y2R interaction with integrins in nucleotide-induced chemotaxis. Here we show that mutation of the RGD sequence to RGE in the human P2Y2R expressed in 1321N1 astrocytoma cells completely prevented UTP-induced chemotaxis as well as activation of GO, Rac, and Vav2, a guanine nucleotide exchange factor for Rac. UTP also increased expression of vitronectin, an extracellular matrix protein that is a ligand for αvβ3/ β5 integrins, in cells expressing the wild-type but not the RGE mutant P2Y2R. P2Y2R-mediated chemotaxis, Rac and Vav2 activation, and vitronectin up-regulation were inhibited by pretreatment of the cells with anti-αvβ5 integrin antibodies, αv integrin antisense oligonucleotides, or the Gi/o inhibitor, pertussis toxin. Thus, the RGD-dependent interaction between the P2Y2R and αv integrins is necessary for the P2Y 2R to activate Go and to initiate Go-mediated signaling events leading to chemotaxis.

Original languageEnglish (US)
Pages (from-to)39050-39057
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number47
DOIs
StatePublished - Nov 25 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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