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Vol. 19, Issue 10, 4188-4200, October 2008

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G Protein-coupled Receptor-promoted Trafficking of Gβ₁₂ Leads to AKT Activation at Endosomes via a Mechanism Mediated by Gβ₁₂-Rab11a Interaction

Alejandro García-Regalado^*, María Luisa Guzmán-Hernández, Iliana Ramírez-Rangel, Evelyn Robles-Molina, Tamas Balla, José Vázquez-Prado, and Guadalupe Reyes-Cruz^*

Departments of *Cell Biology and Pharmacology, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, 07000 México, D.F., México; and Section on Molecular Signal Transduction, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510

Submitted October 30, 2007; Revised July 16, 2008; Accepted August 6, 2008
Monitoring Editor: J. Silvio Gutkind

G-protein coupled receptors activate heterotrimeric G proteins at the plasma membrane in which most of their effectors are intrinsically located or transiently associated as the external signal is being transduced. This paradigm has been extended to the intracellular compartments by studies in yeast showing that trafficking of G activates phosphatidylinositol 3-kinase (PI3K) at endosomal compartments, suggesting that vesicle trafficking regulates potential actions of G and possibly Gβ at the level of endosomes. Here, we show that Gβ interacts with Rab11a and that the two proteins colocalize at early and recycling endosomes in response to activation of lysophosphatidic acid (LPA) receptors. This agonist-dependent association of Gβ to Rab11a-positive endosomes contributes to the recruitment of PI3K and phosphorylation of AKT at this intracellular compartment. These events are sensitive to the expression of a dominant-negative Rab11a mutant or treatment with wortmannin, suggesting that Rab11a-dependent Gβ trafficking promotes the activation of the PI3K/AKT signaling pathway associated with endosomal compartments. In addition, RNA interference-mediated Rab11a depletion, or expression of a dominant-negative Rab11a mutant attenuated LPA-dependent cell survival and proliferation, suggesting that endosomal activation of the PI3K/AKT signaling pathway in response to Gβ trafficking, via its interaction with Rab11, is a relevant step in the mechanism controlling these fundamental events.

Address correspondence to: Guadalupe Reyes-Cruz (guadaluper{at}cell.cinvestav.mx)

Abbreviations used: EEA1, early endosomal antigen 1; GPCR, G protein coupled receptor; LPA, lysophosphatidic acid; PhLP1, phosducin-like protein 1; PI3-kinase, phosphoinositide 3-kinase; Wm, wortmannin.

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