G Protein-coupled Receptor-promoted Trafficking of G 1 2 Leads to AKT Activation at Endosomes via a Mechanism Mediated by G 1 2-Rab11a Interaction

Department of Cell Biology, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, 07000 México, DF, México.
Molecular biology of the cell (Impact Factor: 4.47). 09/2008; 19(10):4188-200. DOI: 10.1091/mbc.E07-10-1089
Source: PubMed


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 Galpha activates phosphatidylinositol 3-kinase (PI3K) at endosomal compartments, suggesting that vesicle trafficking regulates potential actions of Galpha and possibly Gbetagamma at the level of endosomes. Here, we show that Gbetagamma 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 Gbetagamma 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 Gbetagamma 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 Gbetagamma trafficking, via its interaction with Rab11, is a relevant step in the mechanism controlling these fundamental events.

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Available from: Jose Vazquez-Prado, Sep 15, 2014
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    • "It is interesting to speculate that endosomal pH might coordinate PI3K-Akt signaling by modulating the protonation and charge status of the signaling components. Early endosomes, including the Rab5-positive compartment and EEA1-positive fraction, are well documented as a potential location where intrinsic signaling arises (Garcia-Regalado et al., 2008; Sigismund et al., 2008; Sorkin and von Zastrow, 2009). Recent studies reveal the involvement of late endosomes/lysosomes in endosomal signaling (Flinn et al., 2010; Sancak et al., 2010; Taelman et al., 2010; Zoncu et al., 2011; Dobrowolski et al., 2012; Jewell membrane in Chinese hamster ovary cells (Presley et al., 1997). "
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    Frontiers in Physiology 01/2014; 4:412. DOI:10.3389/fphys.2013.00412 · 3.53 Impact Factor
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    • "Active PI3k catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP(3)) at the plasma membrane, which in turn promotes the recruitment and activation of Akt at the membrane [15]. Akt is a serine/threonine kinase that plays a key role in multiple cellular processes, such as proliferation, survival and cell invasion [16]. Over-activation of Akt influences multiple downstream effectors, including inactivation of proapoptotic factors such as Bad and caspase-9 [17,18]. "
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