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
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
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-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
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-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-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,
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Association of CPI-17 with protein kinase C and casein kinase I.
Biochemical and biophysical research communications 2004 Mar 26;316(1):39-47
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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
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Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway.
The EMBO journal 2003 Jan 2;22(1):109-20
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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
- 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
- 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
- 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
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The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation.
The EMBO journal 1999 Jun 1;18(11):3044-53
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Protein kinase C-theta (PKCtheta): it's all about location, location, location.
Immunological reviews 2003 Apr;192:53-63
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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
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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
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Protein kinase cascades in the regulation of cardiac hypertrophy.
The Journal of clinical investigation 2005 Mar;115(3):527-37