Department of Pharmacology and Program in Vascular Biology and Therapeutics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Nat Cell Biol. 2012 May 20;14(7):686-96. doi: 10.1038/ncb2507.
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 Gα(12), 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 Gα(12)-mediated signalling pathway for mTORC2 regulation is critically important for fibroblast migration and pulmonary fibrosis development.
哺乳动物雷帕霉素靶蛋白复合物 2（mTORC2）磷酸化 AGC 蛋白激酶，包括蛋白激酶 C（PKC），并调节细胞迁移等细胞功能。然而，其调控机制仍知之甚少。本文作者表示，溶血磷脂酸（LPA）可诱导 PKC-δ 疏水性基序发生两阶段磷酸化。晚期阶段由 Gα(12)介导，其特异性激活 ARAF，导致 RFFL E3 泛素连接酶上调，随后 mTORC2 的 PRR5L 亚基泛素化和降解。PRR5L 是抑制 PKC-δ 与 mTORC2 介导的疏水性基序磷酸化的负调控因子，其不稳定会导致 PKC-δ 疏水性基序磷酸化和激活。这种 Gα(12)介导的 mTORC2 调控信号通路对成纤维细胞迁移和肺纤维化发展至关重要。
