PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12
Copyright policy )PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12
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.
- University of California, San Diego United States
- University of Tokyo Japan
- National Cancer Institute United States
- Max Planck Society Germany
- University of California, San Francisco United States
570, Amino Acid Motifs, 610, Mechanistic Target of Rapamycin Complex 2, GTP-Binding Protein alpha Subunits, G12-G13, Article, Bleomycin, Mice, Cell Movement, Enzyme Stability, Animals, Humans, Extracellular Signal-Regulated MAP Kinases, Lung, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Fibroblasts, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, HEK293 Cells, Lysophospholipids, Apoptosis Regulatory Proteins
570, Amino Acid Motifs, 610, Mechanistic Target of Rapamycin Complex 2, GTP-Binding Protein alpha Subunits, G12-G13, Article, Bleomycin, Mice, Cell Movement, Enzyme Stability, Animals, Humans, Extracellular Signal-Regulated MAP Kinases, Lung, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Fibroblasts, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, HEK293 Cells, Lysophospholipids, Apoptosis Regulatory Proteins
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