Abstract
Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates AGC protein kinases including protein kinase C (PKC) and regulates cellular functions such as cell migration. However, its regulation remains poorly understood. Here we show that lysophosphatidic acid (LPA) induces two phases of PKC-δ hydrophobic motif phosphorylation. The late phase is mediated by Gα12, which specifically activates ARAF, leading to upregulation of the RFFL E3 ubiquitin ligase and subsequent ubiquitylation and degradation of the PRR5L subunit of mTORC2. Destabilization of PRR5L, a suppressor of mTORC2-mediated hydrophobic motif phosphorylation of PKC-δ, but not AKT, results in PKC-δ hydrophobic motif phosphorylation and activation. This Gα12-mediated signalling pathway for mTORC2 regulation is critically important for fibroblast migration and pulmonary fibrosis development.
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Acknowledgements
We thank B. Su for discussion and the anti-MAPKAP1 antibody, and M. Orsulak for technical help. This work is supported by National Institutes of Health grants (HL070694, HL080706 and CA139395 to D.W. and GM61454 and GM074001 to T.K.) and an Ellison Medical Foundation grant (AG-SS-2190-08 to M.I.S.).
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X.G. conceived the initial idea, planned and carried out some of the experiments, analysed the data and participated in manuscript preparation. J.W. and C.W. carried out some of the experiments. E.S., T.K., S.S. and D.A. provided experimental materials. S.O. and M.I.S. provided research materials and comments and helped in manuscript preparation. D.W. conceived the initial idea, planed the experiments, analysed the data and prepared the manuscript.
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Gan, X., Wang, J., Wang, C. et al. PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12. Nat Cell Biol 14, 686–696 (2012). https://doi.org/10.1038/ncb2507
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DOI: https://doi.org/10.1038/ncb2507
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