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

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 [1].

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 [2].

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 [3]. Activation of PKC-mu in response to oxidative stress requires its sequential phosphorylation by two kinases, tyrosine kinase cABL and PKC-delta [4]. PKC-mu activation leads to the transcriptional activation of NUR77 via Myocyte enhancer factor 2 (MEF2)-binding sites in its promoter [5].

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

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

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 [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 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 [10].

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 [11]. GSK3-beta phosphorylates conserved serines of NF-AT. This phosphorylation promotes the nuclear exit of NF-AT, thereby opposing Ca(2+)-Calcineurin signaling [12].

References:

1. Zemlickova E, Johannes FJ, Aitken A, Dubois T
   Association of CPI-17 with protein kinase C and casein kinase I. Biochemical and biophysical research communications 2004 Mar 26;316(1):39-47
2. Li J, O'Connor KL, Hellmich MR, Greeley GH Jr, Townsend CM Jr, Evers BM
   The role of protein kinase D in neurotensin secretion mediated by protein kinase C-alpha/-delta and Rho/Rho kinase. The Journal of biological chemistry 2004 Jul 2;279(27):28466-74
3. Storz P, Toker A
   Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway. The EMBO journal 2003 Jan 2;22(1):109-20
4. Storz P, Doppler H, Toker A
   Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling. Molecular and cellular biology 2004 Apr;24(7):2614-26
5. Parra M, Kasler H, McKinsey TA, Olson EN, Verdin E
   Protein kinase D1 phosphorylates HDAC7 and induces its nuclear export after T-cell receptor activation. The Journal of biological chemistry 2005 Apr 8;280(14):13762-70
6. Wooten MW, Vandenplas ML, Seibenhener ML, Geetha T, Diaz-Meco MT
   Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C's via a src kinase pathway. Molecular and cellular biology 2001 Dec;21(24):8414-27
7. Wang YM, Seibenhener ML, Vandenplas ML, Wooten MW
   Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF-kappaB/JNK kinase and cell survival. Journal of neuroscience research 1999 Feb 1;55(3):293-302
8. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J
   The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. The EMBO journal 1999 Jun 1;18(11):3044-53
9. Altman A, Villalba M
   Protein kinase C-theta (PKCtheta): it's all about location, location, location. Immunological reviews 2003 Apr;192:53-63
10. Hamilton M, Liao J, Cathcart MK, Wolfman A
    Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. The Journal of biological chemistry 2001 Aug 3;276(31):29079-90
11. Fang X, Yu S, Tanyi JL, Lu Y, Woodgett JR, Mills GB
    Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. Molecular and cellular biology 2002 Apr;22(7):2099-110
12. Dorn GW 2nd, Force T
    Protein kinase cascades in the regulation of cardiac hypertrophy. The Journal of clinical investigation 2005 Mar;115(3):527-37