id: PW:0000840 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000840 title: protein kinase c (pkc) signaling pathway description_xrefs: - GO:0070528 description: 'The protein kinase C family (PKC) comprises ~2% of the human kinome and can be subdivided into three subclasses: conventional or classical (cPKC), novel (nPKC) and atypical (aPKC). All isoforms contain a C-terminal kinase domain and an N-terminal autoinhibitory pseudosubstrate but differ in their responsiveness to second messengers. A tandem DAG-sensitive C1 domain is present in cPKC and nPKC with the latter group displaying a higher sensitivity. The C2 domain is Ca2+ sensitive in cPKC only. Thesingle C1domain in aPKC is DAG-insensitive; this group depends on other lipids or protein-protein interactions for functional regulation. Collectively, the pathway regulates cell proliferation, differentiation, polarity and death and plays a role in the cardiac, immune and nervous systems. PKC signaling is initiated downstream of ligand-activated G protein coupled receptors (GPCR) that trigger the signal transduction mediated by the Galphaq family of heterotrimeric G proteins. The Galphaq activates the beta subtype of phospholipase C (PLC; PLC-B). Other PLC subtypes can be activated downstream of receptor tyrosine kinases (RTK) with potential role in PKC activation. PLC catalyzes the hydrolysis of PIP2 to produce DAG and IP3; IP3 promotes calcium release from ER. Calcium permeates almost every aspect of cellular processes - its uptake, storage, release, buffering and sensing is mediated by a broad range of transporters and channels, calcium-binding and signaling molecules that together constitute the ''calcium signaling kit'' within the two inextricably connected pathways of calcium transport and signaling. Newly synthesized PKCs need priming for maturation - a process that involves a series of tightly controlled phosphorylation events. The Hsp90 chaperone and Cdc37co-chaperone are required for the proper processing of cPKC and nPKCs. Pdpk1 phosphorylates the activation loop of PLC, an event that is constitutive for cPKC and nPKCs but agonist dependent for aPKCs. A second phosphorylation at the turn motif, completes the maturation of PKC and is dependent on mTORC2 complex. Whether the role of mTORC2 is direct or indirect, via activation of an upstream kinase, is currently unclear. Mature, fully phosphorylated PKCs are in the cytoplasm and bound to the autoinhibitory pseudosubstrate. Signals that release calcium facilitate recruitment to the plasma membrane followed by DAG binding or there is direct membrane recruitment via high DAG affinity. At the membrane, PKC is in an open conformation which promotes release of pseudosubstrate and binding of a variety of interactors - adaptors or scaffolds and other binding partners and substrates, in order to fulfill many cellular tasks. The open conformation can also promotes dephosphorylation by members of PPM phosphatase family. Dephosphorylated PKC is sequestered in insoluble fraction for further dephosphorylation and subsequent degradation. However, it can also be bound by HSP70 which promotes its re-phosphorylation and re-enter into the signaling cycle. Internalization of receptors and conversion of DAG to PA by DGKs terminates signaling (not shown). Deregulation of PKC signaling pathway has been implicated in tumorigenesis and neurodegeneration.' diagram_image: https://rgd.mcw.edu/pathway/PW0000840/protein%20kinase%20C%20(PKC)%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000840/protein%20kinase%20C%20(PKC)%20signaling%20pathway/protein%20kinase%20C%20(PKC)%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000229 label: G protein mediated signaling pathway via Galphaq family - id: PW:0001139 label: calcium transport pathway - id: PW:0001140 label: calcium/calcium-mediated signaling pathway diagram_gene_links: - id: RGD:71006 label: Cdc37 - id: RGD:631409 label: Hsp90aa1 - id: RGD:620307 label: Pdpk1 - id: RGD:621308 label: Phlpp1 - id: RGD:1562857 label: Phlpp2 diagram_chemicals: - id: CHEBI:29108 label: Ca2+ - id: CHEBI:18035 label: DAG - id: CHEBI:16595 label: IP3 - id: PUBCHEM.SUBSTANCE:135651544 label: PIP2 diagram_edges: - source: Ca2+ relation: associated_with target: cPKC - source: Cdc37 relation: associated_with target: cPKC - source: Cdc37 relation: associated_with target: nPKC - source: DAG relation: associated_with target: nPKC - source: Hsp90aa1 relation: associated_with target: nPKC - source: PIP2 relation: positively_affects target: DAG - source: PIP2 relation: positively_affects target: IP3 - source: Phlpp1 relation: negatively_affects target: cPKC - source: Phlpp1 relation: negatively_affects target: nPKC - source: Phlpp2 relation: negatively_affects target: cPKC - source: Phlpp2 relation: negatively_affects target: nPKC - source: aPKC relation: associated_with target: PKC interactors - source: aPKC relation: positively_affects target: cell polarity - source: cPKC relation: associated_with target: DAG - source: cPKC relation: associated_with target: Hsp90aa1 - source: cPKC relation: associated_with target: PKC interactors - source: cPKC relation: positively_affects target: cell death - source: cPKC relation: positively_affects target: cell differentiation - source: cPKC relation: positively_affects target: cell proliferation - source: nPKC relation: associated_with target: PKC interactors - source: nPKC relation: positively_affects target: cell death - source: nPKC relation: positively_affects target: cell differentiation - source: nPKC relation: positively_affects target: cell proliferation diagram_labels: - cell death - cell differentiation - cell polarity - cell proliferation - GPCRs upstream PKC --+> PLC-B members - IP3 --+> Ca2+ - Pdpk1 --+> aPKC - Pdpk1 --+> cPKC - Pdpk1 --+> nPKC diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/atypical-pkc label: aPKC - href: /wg/home/pathway2/molecular-pathways2/conventional-pkc label: cPKC - href: /wg/home/pathway2/molecular-pathways2/novel-pkc label: nPKC - href: /wg/home/pathway2/molecular-pathways2/pkc-interactors label: PKC interactors - href: /wg/home/pathway2/molecular-pathways2/plc-b-members label: PLC-B members - href: /wg/home/pathway2/molecular-pathways2/upstream-pathways-activating-pkc-intracellular-signaling label: GPCRs upstream PKC references: - id: RGD:5131488 citation: Gallegos LL and Newton AC, IUBMB Life. 2008 Dec;60(12):782-9. - id: RGD:5131489 citation: Newton AC Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E395-402. Epub 2009 Nov 24. - id: RGD:5131490 citation: Rosse C, etal., Nat Rev Mol Cell Biol. 2010 Feb;11(2):103-12. - id: RGD:5131491 citation: Walker JW Handb Exp Pharmacol. 2008;(186):185-203. - id: RGD:5131492 citation: Poole AW, etal., Trends Pharmacol Sci. 2004 Oct;25(10):528-35. - id: RGD:5131493 citation: Kheifets V and Mochly-Rosen D, Pharmacol Res. 2007 Jun;55(6):467-76. Epub 2007 May 3. - id: RGD:5131494 citation: Schechtman D and Mochly-Rosen D, Oncogene. 2001 Oct 1;20(44):6339-47. - id: RGD:5131495 citation: Rhee SG Annu Rev Biochem. 2001;70:281-312. - id: RGD:5131496 citation: Suh PG, etal., BMB Rep. 2008 Jun 30;41(6):415-34. - id: RGD:5131497 citation: Brognard J and Newton AC, Trends Endocrinol Metab. 2008 Aug;19(6):223-30. Epub 2008 May 27. - id: RGD:5131498 citation: Giorgi C, etal., Antioxid Redox Signal. 2010 Oct 1;13(7):1051-85. - id: RGD:5131499 citation: Hubbard KB and Hepler JR, Cell Signal. 2006 Feb;18(2):135-50. Epub 2005 Sep 22. - id: RGD:5131500 citation: Mizuno N and Itoh H, Neurosignals. 2009;17(1):42-54. Epub 2009 Feb 12. - id: RGD:5131502 citation: Drin G and Scarlata S, Cell Signal. 2007 Jul;19(7):1383-92. Epub 2007 Apr 29. - id: RGD:5132275 citation: Suzuki A and Ohno S, J Cell Sci. 2006 Mar 15;119(Pt 6):979-87. - id: RGD:5143917 citation: Merida I, etal., Biochem J. 2008 Jan 1;409(1):1-18. - id: RGD:5143918 citation: Sklan EH, etal., Prog Neurobiol. 2006 Feb;78(2):117-34. Epub 2006 Feb 2.