PRR5L degradation promotes mTORC2-mediated PKC-? phosphorylation and cell migration downstream of G?12.
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-? hydrophobic motif phosphorylation. The late phase is mediated ... by G?(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-?, but not AKT, results in PKC-? hydrophobic motif phosphorylation and activation. This G?(12)-mediated signalling pathway for mTORC2 regulation is critically important for fibroblast migration and pulmonary fibrosis development.
Mesh Terms:
Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Bleomycin, Cell Movement, Disease Models, Animal, Enzyme Activation, Enzyme Stability, Extracellular Signal-Regulated MAP Kinases, Fibroblasts, GTP-Binding Protein alpha Subunits, G12-G13, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Lung, Lysophospholipids, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Phosphorylation, Protein Kinase C-delta, Protein Stability, Proteins, Proto-Oncogene Proteins c-akt, Pulmonary Fibrosis, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Time Factors, Trans-Activators, Transfection, Ubiquitin-Protein Ligases, Ubiquitination
Amino Acid Motifs, Animals, Apoptosis Regulatory Proteins, Bleomycin, Cell Movement, Disease Models, Animal, Enzyme Activation, Enzyme Stability, Extracellular Signal-Regulated MAP Kinases, Fibroblasts, GTP-Binding Protein alpha Subunits, G12-G13, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Lung, Lysophospholipids, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes, Phosphorylation, Protein Kinase C-delta, Protein Stability, Proteins, Proto-Oncogene Proteins c-akt, Pulmonary Fibrosis, RNA Interference, Signal Transduction, TOR Serine-Threonine Kinases, Time Factors, Trans-Activators, Transfection, Ubiquitin-Protein Ligases, Ubiquitination
Nat Cell Biol
Date: May. 20, 2012
PubMed ID: 22609986
View in: Pubmed Google Scholar
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