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First published online April 23, 2007
doi: 10.1242/10.1242/jcs.03441

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The P2Y₂ nucleotide receptor requires interaction with v integrins to access and activate G₁₂

Department of Biochemistry, Life Sciences Center, University of Missouri-Columbia, Columbia, MO 65211, USA

^* Author for correspondence (e-mail: erbl{at}missouri.edu)

Accepted 7 March 2007

The P2Y₂ nucleotide receptor (P2Y₂R) interacts with v integrins to activate G_o and induce chemotaxis in human 1321N1 astrocytoma cells. In this study, it was determined that the P2Y₂R also requires interaction with v integrins to activate G₁₂ and associated signaling pathways that control chemotaxis in 1321N1 cells. Mutation of the Arg-Gly-Asp (RGD) integrin-binding sequence in the first extracellular loop of the human P2Y₂R to Arg-Gly-Glu (RGE), which prevents integrin interaction, did not inhibit G_q or ERK1/2 signaling by the P2Y₂R agonist UTP but completely inhibited activation of G₁₂ and G₁₂-mediated events, including Rho activation, cofilin and myosin light chain-2 phosphorylation, stress fiber formation and chemotaxis towards UTP. The involvement of G₁₂ in all these events was verified by using a dominant negative G₁₂ construct. G₁₂ activation by the P2Y₂R also was inhibited by anti-v5 integrin antibodies and v integrin antisense oligonucleotides, suggesting that v integrin activity and expression are required for the P2Y₂R to activate G₁₂. Co-immunoprecipitation experiments confirmed that G₁₂ protein associates with the wild-type P2Y₂R and with v integrins but not with the RGE mutant P2Y₂R or with 3 integrins. Collectively, these results suggest that v integrin complexes provide the P2Y₂R with access to G₁₂, thereby allowing activation of this heterotrimeric G protein that controls actin cytoskeletal rearrangements required for chemotaxis.

Key words: P2Y₂ receptor, G₁₂, v integrin, Cell migration, Stress fibers

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