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Lipid kinase
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Signal transduction Activation of PKC via G-Protein coupled receptor


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Signal transduction Activation of PKC via G-Protein coupled receptor

PKC family signaling

The family of Protein kinase C ( PKC ) contains 3 functionalprotein types, 'conventional' PKC-alpha, PKC-beta, and PKC-gammathat are activated by calcium and Diacylglycerol ( DAG ), 'novel' PKC-delta, PKC-epsilon, PKC-eta, and PKC-theta that are activated byDAG only, and 'atypical' PKC-iota, PKC-zeta, and PKC-muthat are not activated by calcium and DAG.

When activated by biomechanical stress or neurohormonal mediators,G-protein coupled receptors separate heterotrimeric G-proteins to G-proteinalpha-q/11 subunits and heterodimeric G-protein beta/gamma subunits.G-proteins bind and activate Phospholipase C beta ( PLC-beta ), recruitPLC-beta to the membrane where it hydrolyses Phosphatidylinositol 4,5 bisphosphate( PtdIns(4,5)P2 ) and releases Inositol 1,4,5-triphosphate ( IP3 ) andDAG. IP3 binds to receptors ( IP3R ) in the endoplasmic reticulum,releasing calcium ( Ca(2+) ). The increase in cytosolic Ca(2+) activatesthe protein phosphatase Calcineurin. Calcineurin dephosphorylates severalresidues in the amino-terminal region of the transcription factor NF-AT, allowingit to translocate to the nucleus and activate transcription of hypertrophic responsegenes.

PKC-alpha, PKC-delta, PKC-epsilon,PKC-zeta and PKC-mu phosphorylate and activate PKC-potentiated inhibitorprotein of 17kDa ( CPI-17 ). CPI-17 specifically inhibits myosin lightchain phosphatase ( MLCP ), leading to MELC phosphorylation by MLCK. MLCK in turn is activated by Calmodulin [1].

One of the PKC-regulated pathways leads to the inhibition of a subsetof Histone deacetylases ( HDAC7 ) that specifically regulate cellular hypertrophy.In this pathway, PKC-delta activates another protein kinase, PKC-mu, thatin its turn phosphorylates the HDAC7 leading to its export from the nucleus andconsequent inactivation [2].

PKC-mu activates the transcription factor Nuclear factor kappaB( NF-kB ). PKC-mu phosphorylates the IKK beta, leading toI-kB degradation and subsequent NF-kB translocation into the nucleus [3]. Activation of PKC-mu in response to oxidative stress requires itssequential phosphorylation by two kinases, tyrosine kinase cABL andPKC-delta [4]. PKC-mu activation leads to the transcriptionalactivation of NUR77 via Myocyte enhancer factor 2 ( MEF2 )-binding sites inits promoter [5].

v-Src sarcoma viral oncogene homolog ( c-Src ) phosphorylatesand activates PKC-iota [6].

Atypical PKC-zeta is activated by Ceramide. This resultsin activation of NF-kB and continued survival of the cell [7].

The two members of the atypical protein kinase C (aPKC) subfamily ofisozymes ( PKC-zeta and PKC-iota ) are involved in control of theNF-kB activity through IKKbeta activation. aPKC-binding proteinSequestosome 1(p62) selectively interacts with receptor-interacting proteinRIPK1 as an adaptor. Sequestosome 1(p62) bridges atypical PKCs andRIPK1. The latter activates IKK gamma, and atypical PKCs phosphorylate andactivate IKKbeta. Thereby, the interactions of Sequestosome 1(p62) withRIPK1 and the atypical PKCs lead to the activation of NF-kB signalingpathway [8].

The PKC-theta isoform also induces NF-kB activation.PKC-theta directly targets IKK beta for phosphorylation and activation,possibly via homodimeric IKKbeta complexes [9].

PKC-alpha, PKC-beta, PKC-gamma,PKC-epsilon, and PKC-eta phosphorylate and activate v-Raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1 ) leading to the stimulation of theMitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/Mitogen-activated protein kinases 1 and 3 ( ERK1/2 ) cascade and activation of thetranscription factor Elk-1 [10].

Several PKC isotypes ( PKC-alpha, PKC-beta,PKC-gamma, PKC-delta, and PKC-eta ) phosphorylate Glycogensynthase kinase 3 beta ( GSK3-beta ) and inactivate it [11].GSK3-beta phosphorylates conserved serines of NF-AT. This phosphorylationpromotes the nuclear exit of NF-AT, thereby opposing Ca(2+) -Calcineurin signaling [12].