title: PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12.
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.
authors.affiliation: Department of Pharmacology and Program in Vascular Biology and Therapeutics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Gan
authors.forename: Jiyong
authors.initials: J
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Eeva
authors.initials: E
authors.lastname: Sommer
authors.forename: Tohru
authors.initials: T
authors.lastname: Kozasa
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Srinivasula
authors.forename: Dario
authors.initials: D
authors.lastname: Alessi
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Melvin I
authors.initials: MI
authors.lastname: Simon
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001761:Bleomycin; D002465:Cell Movement; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004795:Enzyme Stability; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D008246:Lysophospholipids / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D046912:Multiprotein Complexes; D011506:Proteins; D015534:Trans-Activators; C562322:protor-2 protein, mouse; D001761:Bleomycin; C502761:Rffl protein, mouse; D044767:Ubiquitin-Protein Ligases; C497259:Prkcd protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C032881:lysophosphatidic acid