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 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Apoptosis Regulatory Proteins
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Bleomycin
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Cell Movement
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Disease Models, Animal
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Enzyme Activation
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Enzyme Stability
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / enzymology*
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Fibroblasts / pathology
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GTP-Binding Protein alpha Subunits, G12-G13 / deficiency
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GTP-Binding Protein alpha Subunits, G12-G13 / genetics
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GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Lung / enzymology
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Lung / pathology*
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Lysophospholipids / metabolism
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / metabolism*
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Phosphorylation
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Protein Kinase C-delta / genetics
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Protein Kinase C-delta / metabolism*
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Protein Stability
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Proteins / genetics
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Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / enzymology*
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / pathology
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RNA Interference
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Signal Transduction
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TOR Serine-Threonine Kinases / metabolism*
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Time Factors
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transfection
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Ubiquitin-Protein Ligases
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Ubiquitination
Substances
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Apoptosis Regulatory Proteins
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Intracellular Signaling Peptides and Proteins
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Lysophospholipids
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Multiprotein Complexes
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Proteins
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Trans-Activators
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protor-2 protein, mouse
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Bleomycin
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Rffl protein, mouse
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Ubiquitin-Protein Ligases
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Prkcd protein, mouse
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Protein Kinase C-delta
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Extracellular Signal-Regulated MAP Kinases
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GTP-Binding Protein alpha Subunits, G12-G13
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lysophosphatidic acid