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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.

Titel:	PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12.
Autor/in / Beteiligte Person:	Gan, X ; Wang, J ; Wang, C ; Sommer, E ; Kozasa, T ; Srinivasula, S ; Alessi, D ; Offermanns, S ; Simon, MI ; Wu, D
Zeitschrift:	Nature cell biology, Jg. 14 (2012-05-20), Heft 7, S. 686-96
Veröffentlichung:	London : Macmillan Magazines Ltd., [1999-, 2012
Medientyp:	academicJournal
ISSN:	1476-4679 (electronic)
DOI:	10.1038/ncb2507
Schlagwort:	Amino Acid Motifs Animals Apoptosis Regulatory Proteins Bleomycin Cell Movement Disease Models, Animal Enzyme Activation Enzyme Stability Extracellular Signal-Regulated MAP Kinases metabolism Fibroblasts pathology GTP-Binding Protein alpha Subunits, G12-G13 deficiency GTP-Binding Protein alpha Subunits, G12-G13 genetics HEK293 Cells Humans Intracellular Signaling Peptides and Proteins Lung enzymology Lysophospholipids metabolism Mechanistic Target of Rapamycin Complex 2 Mice Mice, Inbred C57BL Mice, Knockout Phosphorylation Protein Kinase C-delta genetics Protein Stability Proteins genetics Proto-Oncogene Proteins c-akt metabolism Pulmonary Fibrosis chemically induced Pulmonary Fibrosis genetics Pulmonary Fibrosis pathology RNA Interference Signal Transduction Time Factors Trans-Activators genetics Transfection Ubiquitin-Protein Ligases Ubiquitination Fibroblasts enzymology GTP-Binding Protein alpha Subunits, G12-G13 metabolism Lung pathology Multiprotein Complexes metabolism Protein Kinase C-delta metabolism Proteins metabolism Pulmonary Fibrosis enzymology TOR Serine-Threonine Kinases metabolism Trans-Activators metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Nat Cell Biol] 2012 May 20; Vol. 14 (7), pp. 686-96. <i>Date of Electronic Publication: </i>2012 May 20. MeSH Terms: Fibroblasts / enzymology ; GTP-Binding Protein alpha Subunits, G12-G13 / metabolism ; Lung / pathology ; Multiprotein Complexes / metabolism ; Protein Kinase C-delta / metabolism ; Proteins / metabolism ; Pulmonary Fibrosis / enzymology ; TOR Serine-Threonine Kinases / metabolism ; Trans-Activators / *metabolism ; Amino Acid Motifs ; Animals ; Apoptosis Regulatory Proteins ; Bleomycin ; Cell Movement ; Disease Models, Animal ; Enzyme Activation ; Enzyme Stability ; Extracellular Signal-Regulated MAP Kinases / metabolism ; Fibroblasts / pathology ; GTP-Binding Protein alpha Subunits, G12-G13 / deficiency ; GTP-Binding Protein alpha Subunits, G12-G13 / genetics ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Lung / enzymology ; Lysophospholipids / metabolism ; Mechanistic Target of Rapamycin Complex 2 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Protein Kinase C-delta / genetics ; Protein Stability ; Proteins / genetics ; Proto-Oncogene Proteins c-akt / metabolism ; Pulmonary Fibrosis / chemically induced ; Pulmonary Fibrosis / genetics ; Pulmonary Fibrosis / pathology ; RNA Interference ; Signal Transduction ; Time Factors ; Trans-Activators / genetics ; Transfection ; Ubiquitin-Protein Ligases ; Ubiquitination References: Cell. 2006 Oct 6;127(1):125-37. 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(PMID: 19244117) Grant Information: CA139395 United States CA NCI NIH HHS; HL080706 United States HL NHLBI NIH HHS; P01 HL070694-09 United States HL NHLBI NIH HHS; MC_U127070193 United Kingdom MRC_ Medical Research Council; R01 GM074001 United States GM NIGMS NIH HHS; R01 HL120465 United States HL NHLBI NIH HHS; R01 GM054597 United States GM NIGMS NIH HHS; R01 CA139395-04 United States CA NCI NIH HHS; R01 CA139395 United States CA NCI NIH HHS; R01 HL108430 United States HL NHLBI NIH HHS; GM074001 United States GM NIGMS NIH HHS; MC_U127015387 United Kingdom MRC_ Medical Research Council; GM61454 United States GM NIGMS NIH HHS; R01 GM061454 United States GM NIGMS NIH HHS; HL070694 United States HL NHLBI NIH HHS; R01 HL080706 United States HL NHLBI NIH HHS; P01 HL070694 United States HL NHLBI NIH HHS; R01 HL108430-01A1 United States HL NHLBI NIH HHS Substance Nomenclature: 0 (Apoptosis Regulatory Proteins) ; 0 (Intracellular Signaling Peptides and Proteins) ; 0 (Lysophospholipids) ; 0 (Multiprotein Complexes) ; 0 (Proteins) ; 0 (Trans-Activators) ; 0 (protor-2 protein, mouse) ; 11056-06-7 (Bleomycin) ; EC 2.3.2.27 (Rffl protein, mouse) ; EC 2.3.2.27 (Ubiquitin-Protein Ligases) ; EC 2.7.1.- (Prkcd protein, mouse) ; EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) ; EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) ; EC 2.7.11.1 (TOR Serine-Threonine Kinases) ; EC 2.7.11.13 (Protein Kinase C-delta) ; EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) ; EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, G12-G13) ; PG6M3969SG (lysophosphatidic acid) Entry Date(s): Date Created: 20120522 Date Completed: 20120907 Latest Revision: 20220129 Update Code: 20231215 PubMed Central ID: PMC3389271

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PRR5L degradation promotes mTORC2-mediated PKC-δ phosphorylation and cell migration downstream of Gα12.