PRR5L degradation promotes MTORC2-mediated PKCδ phosphorylation and cell migration downstream of Gα12

Mammalian target of rapamycin complex (MTORC) 2 phosphorylates AGC protein kinases including PKC and regulates cellular functions including cell migration. However, its regulation remains poorly understood. Here we show that LPA induces two phases of PKCδ hydrophobic motif (HM) phosphorylation. The late phase is mediated by Gα12, which specifically activates ARAF, leading to upregulation of the expression of an E3 ubiquitin ligase RFFL and subsequent ubiquitination and degradation of PRR5L. Destabilization of PRR5L, a suppressor of mTORC2-mediated HM phosphorylation of PKCδ, but not AKT, results in PKCδ HM phosphorylation and activation. This Gα12-mediated pathway is critically important for fibroblast migration and pulmonary fibrosis development. Thus, our study unravels a signaling pathway for mTORC2 regulation and fibroblast migration.