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Tables
Protein Kinase Tables Home
Overview
Protein kinase C (PKC) is a cyclic nucleotide-independent enzyme that phosphorylates serine and threonine residues in
many target proteins. It was first identified in 1977 in bovine cerebellum by Nishizuka and co-workers as a protein kinase
that phosphorylated histone and protamine. Since then, its involvement in many biological processes has been demonstrated,
including development, memory, differentiation, proliferation and carcinogenesis. Once thought to be a single protein, PKC
is now known to comprise a large family of enzymes that differ in structure, cofactor requirements and function.
At present, 10 isoforms have been identified (depending on the classification used), varying in tissue expression and
cellular compartmentalization (allowing for specific interactions with substrates).
The PKC family has been divided into three groups, differing in the enzymes' cofactor requirements: conventional (c)PKC
isoforms (comprising
 ,
I {also known as
2},
II
{also known as 1 } and
 ),
that require calcium and diacylglycerol (DAG) for activation; novel (n)PKC isoforms (comprising
 ,
 ,
 {also known as PKC-L},
 and µ
{the mouse homolog of human PKCµ is known as PKD}) that require DAG; and atypical (a)PKC isoforms,
namely  ,
 and
 (the mouse homolog of human PKC
) that require neither calcium nor DAG.
A new PKC member has recently been discovered and is referred to as PKC
 .
It contains 890 amino acid residues and exhibits highest sequence similarity to PKCµ/PKD thereby posing the
possibility of a fourth subfamily of PKCs, comprising these isoforms. All PKCs possess a phospholipid-binding domain
for membrane interaction. The PKC-related kinases (PRKs) have also been classified as members of the PKC superfamily.
The general structure of a PKC molecule consists of a catalytic and a regulatory domain, composed of a number of conserved
regions, interspersed with regions of lower homology, the variable domains.
Activation of cPKCs involves translocation from the cytosol to binding domains at cell membranes. Specific anchoring
proteins (immobilized at particular intracellular sites) localize the kinase to its site of action. These proteins
include 'receptors for activated C-kinase' (RACKS) and adducins. Following an increase in intracellular calcium levels,
cPKCs interact with the cell membrane in an inactive, but conformationally distinct, form. DAG facilitates penetration
of these isoenzymes into the cell membrane (tumor-promoting phorbol esters are used experimentally as synthetic DAG-analogs).
When attached, the affinity of PKC for calcium is increased such that activation of the enzyme is achieved
(depending on its phosphorylation status). Phosphatidylserine is the membrane lipid anchor for both cPKCs and nPKCs,
although other membrane phospholipids may ultimately link extracellular signals to intracellular events through PKC.
Some, if not all, PKC isoforms can be proteolytically cleaved at the V3 region by the calcium-activated protease,
calpain, to generate a cofactor-independent free catalytic subunit known as protein kinase M (PKM). The physiological
relevance of the 'calpain-product' is that it should not be regarded as an 'unregulated' enzyme since its generation is,
in fact, regulated by proteolysis. Cleavage also takes place during apoptosis.
All PKCs, except the isoform, express
so-called PEST sequences (hydrophilic polypeptide segments enriched in proline (P), glutamic acid (E), serine (S) and
threonine (T)), which target proteins for degradation by the proteasome. An additional level of complexity is apparent
following the observation that dephosphorylation of activated PKCs apparently predispose them to ubiquitination and
degradation.
PKC isoforms are phosphorylated at specific C-terminal serine/threonine residues by phosphatidylinositol-trisphosphate-dependent kinase (PDK1), with at least two additional phosphorylations and/or autophosphorylations of well-conserved sequences in each enzyme of the PKC family. Each phosphorylation event induces conformational changes in the PKC molecule that result in altered thermal stability, resistance to phosphatases and catalytic activity. In addition to general biochemical information, the
Tables list several activators, inhibitors and substrates currently used to examine the roles of PKC
in cellular processes.
Key References:
Dekker, L.V. and Parker, P.J. "Protein kinase C - a question of specificity." Trends Biochem. Sci., 19,
73-77 (1994).
Hug, H. and Sarre, T.F. "Protein kinase C isoenzymes: Divergence in signal transduction?" Biochem. J., 291, 329-343 (1993).
Jaken, S. "Protein kinase C isozymes and substrates." Curr. Opin. Cell Biol., 8, 168-173 (1996).
Jaken, S. and Parker, P.J. "Protein kinase C binding partners." Bioessays, 22.3, 245-254 (2000).
Mellor, H. and Parker, P.J. "The extended protein kinase C superfamily." Biochem. J., 332, 281-292 (1998).
Mochly-Rosen, D. "Localization of protein kinases by anchoring proteins: A theme in signal transduction." Science, 268, 247-251 (1995).
Newton, A.C. "Protein kinase C: Structure, function and regulation." J. Biol. Chem., 270, 28485-28498 (1995).
Newton, A.C. "Regulation of protein kinase C." Curr. Opin. Cell Biol., 9, 161-167 (1997).
Nishizuka, Y. "Protein kinase C and lipid signaling for sustained cellular responses." FASEB. J., 9, 484-496 (1995).
Parekh, D.B., et al. "Multiple pathways control protein kinase C phosphorylation." EMBO J., 19, 496-503 (2000).
Stabel, S. and Parker, P.J. "Protein kinase C." Pharmacol. Ther., 51, 71-95 (1991).
Webb, B.L.J., et al. "Protein kinase C isoenzymes: A review of their structure, regulation and role in regulating airways smooth muscle tone and mito-genesis." Br. J. Pharmacol., 130, 1433-1452 (2000).
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