PLC-beta, MEK1(MAP2K1), <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), DAG, PKC-epsilon, c-Src, MEK2(MAP2K2), NF-AT1(NFATC2), Calcineurin A (catalytic), G-protein beta/gamma, Elk-1, MLCP (reg), MELC, G-protein alpha-q/11, 220.127.116.11, PKC-mu, NUR77, Ceramide, IKK-gamma, MLCK, PKC-eta, PKC-theta, IKK (cat), PKC-zeta, PKC-gamma, I-kB, Ca('2+) endoplasmic reticulum lumen, Calcineurin B (regulatory), PKC-beta, PKC-delta, PtdIns(4,5)P2, c-Abl, CPI-17, RIPK1, HDAC7, Calmodulin, c-Raf-1, PKC-alpha, NF-AT3(NFATC4), MLCP (cat), Erk (MAPK1/3), MEF2, IP3, NF-kB, NF-AT4(NFATC3), PKC-lambda/iota, Ca('2+) cytosol, NF-AT2(NFATC1), Sequestosome 1(p62), GSK3 beta, IP3 receptor, IKK-beta
PKC family signaling
The family of Protein kinase C ( PKC ) contains 3 functional protein types, 'conventional' PKC-alpha, PKC-beta, and PKC-gamma that are activated by calcium and Diacylglycerol ( DAG ), 'novel' PKC-delta, PKC-epsilon, PKC-eta, and PKC-theta that are activated by DAG only, and 'atypical' PKC-iota, PKC-zeta, and PKC-mu that 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-protein alpha-q/11 subunits and heterodimeric G-protein beta/gamma subunits. G-proteins bind and activate Phospholipase C beta ( PLC-beta ), recruit PLC-beta to the membrane where it hydrolyses Phosphatidylinositol 4,5 bisphosphate ( PtdIns(4,5)P2 ) and releases Inositol 1,4,5-triphosphate ( IP3 ) and DAG. IP3 binds to receptors ( IP3R ) in the endoplasmic reticulum, releasing calcium ( Ca(2+) ). The increase in cytosolic Ca(2+) activates the protein phosphatase Calcineurin. Calcineurin dephosphorylates several residues in the amino-terminal region of the transcription factor NF-AT, allowing it to translocate to the nucleus and activate transcription of hypertrophic response genes.
PKC-alpha, PKC-delta, PKC-epsilon, PKC-zeta and PKC-mu phosphorylate and activate PKC-potentiated inhibitor protein of 17kDa ( CPI-17 ). CPI-17 specifically inhibits myosin light chain phosphatase ( MLCP ), leading to MELC phosphorylation by MLCK. MLCK in turn is activated by Calmodulin .
One of the PKC-regulated pathways leads to the inhibition of a subset of Histone deacetylases ( HDAC7 ) that specifically regulate cellular hypertrophy. In this pathway, PKC-delta activates another protein kinase, PKC-mu, that in its turn phosphorylates the HDAC7 leading to its export from the nucleus and consequent inactivation .
PKC-mu activates the transcription factor Nuclear factor kappaB ( NF-kB ). PKC-mu phosphorylates the IKK beta, leading to I-kB degradation and subsequent NF-kB translocation into the nucleus . Activation of PKC-mu in response to oxidative stress requires its sequential phosphorylation by two kinases, tyrosine kinase cABL and PKC-delta . PKC-mu activation leads to the transcriptional activation of NUR77 via Myocyte enhancer factor 2 ( MEF2 )-binding sites in its promoter .
v-Src sarcoma viral oncogene homolog ( c-Src ) phosphorylates and activates PKC-iota .
Atypical PKC-zeta is activated by Ceramide. This results in activation of NF-kB and continued survival of the cell .
The two members of the atypical protein kinase C (aPKC) subfamily of isozymes ( PKC-zeta and PKC-iota ) are involved in control of the NF-kB activity through IKKbeta activation. aPKC-binding protein Sequestosome 1(p62) selectively interacts with receptor-interacting protein RIPK1 as an adaptor. Sequestosome 1(p62) bridges atypical PKCs and RIPK1. The latter activates IKK gamma, and atypical PKCs phosphorylate and activate IKKbeta. Thereby, the interactions of Sequestosome 1(p62) with RIPK1 and the atypical PKCs lead to the activation of NF-kB signaling pathway .
The PKC-theta isoform also induces NF-kB activation. PKC-theta directly targets IKK beta for phosphorylation and activation, possibly via homodimeric IKKbeta complexes .
PKC-alpha, PKC-beta, PKC-gamma, PKC-epsilon, and PKC-eta phosphorylate and activate v-Raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) leading to the stimulation of the Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinases 1 and 3 ( ERK1/2 ) cascade and activation of the transcription factor Elk-1 .
Several PKC isotypes ( PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, and PKC-eta ) phosphorylate Glycogen synthase kinase 3 beta ( GSK3-beta ) and inactivate it . GSK3-beta phosphorylates conserved serines of NF-AT. This phosphorylation promotes the nuclear exit of NF-AT, thereby opposing Ca(2+) - Calcineurin signaling .