Protein kinase C

From Wikipedia, the free encyclopedia

For other uses, see PKC (disambiguation).

Protein kinase C
Identifiers

EC number

2.7.11.13

CAS number

141436-78-4

Databases

IntEnz

IntEnz view

BRENDA

BRENDA entry

ExPASy

NiceZyme view

KEGG

KEGG entry

MetaCyc

metabolic pathway

PRIAM

profile

PDB structures

RCSB PDB PDBe PDBsum

Gene Ontology

AmiGO / EGO

[show]Search

Protein kinase C terminal domain

Identifiers

Symbol

Pkinase_C

Pfam

PF00433

InterPro

IPR017892

[show]Available protein structures:

Protein kinase C also known as PKC (EC 2.7.11.13) is a family of protein kinase enzymes that are
involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups
of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated
by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+).[1].
Hence PKC enzymes play important roles in several signal transduction cascades.
The PKC family consists of fifteen isozymes in humans.[2] They are divided into three subfamilies,
based on their second messenger requirements: conventional (or classical), novel, and atypical.
[3]
Conventional (c)PKCs contain the isoforms , I, II, and . These require Ca2+, DAG, and
a phospholipid such as phosphatidylserine for activation. Novel (n)PKCs include the , , , and
isoforms, and require DAG, but do not require Ca2+ for activation. Thus, conventional and novel
PKCs are activated through the same signal transduction pathway as phospholipase C. On the other
hand, atypical (a)PKCs (including protein kinase M and / isoforms) require neither Ca2+ nor
diacylglycerol for activation. The term "protein kinase C" usually refers to the entire family of
isoforms.
Contents
[hide]

1 Isozymes

2 Structure
o

2.1 Regulatory

2.2 Catalytic

3 Activation

4 Function

5 Pathology

6 Inhibitors

7 See also

8 References

9 External links

Isozymes[edit]

conventional - require DAG, Ca2+, and phospholipid for activation

PKC- (PRKCA)

PKC-1 (PRKCB)

PKC-2 (PRKCB)

PKC- (PRKCG)

novel - require DAG but not Ca2+ for activation

PKC- (PRKCD)

PKC-1 (PRKD1)

PKC-2 (PRKD2)

PKC-3 (PRKD3)

PKC- (PRKCE)

PKC- (PRKCH)

PKC- (PRKCQ)

atypical - require neither Ca2+ nor DAG for activation (require phosphatidyl serine)

PKC- (PRKCI)

PKC- (PRKCZ)

PK-N1 (PKN1)

PK-N2 (PKN2)

PK-N3 (PKN3)

Structure[edit]
The structure of all PKCs consists of a regulatory domain and a catalytic domain tethered together
by a hinge region. The catalytic region is highly conserved among the different isoforms, as well as,
to a lesser degree, among the catalytic region of other serine/threonine kinases. The second
messenger requirement differences in the isoforms are a result of the regulatory region, which are
similar within the classes, but differ among them. Most of the crystal structure of the catalytic region
of PKC has not been determined, except for PKC theta and iota. Due to its similarity to other kinases
whose crystal structure have been determined, the structure can be strongly predicted.

Regulatory[edit]
The regulatory domain or the amino-teminus of the PKCs contains several shared subregions. The
C1 domain, present in all of the isoforms of PKC has a binding site for DAG as well as nonhydrolysable, non-physiological analogues called phorbol esters. This domain is functional and
capable of binding DAG in both conventional and novel isoforms, however, the C1 domain in atypical
PKCs is incapable of binding to DAG or phorbol esters. The C2 domain acts as a Ca 2+ sensor and is
present in both conventional and novel isoforms, but functional as a Ca2+ sensor only in the
conventional. The pseudosubstrate region, which is present in all three classes of PKC, is a small
sequence of amino acids that mimic a substrate and bind the substrate-binding cavity in the catalytic
domain,lack critical serine, threonine phosphoacceptor residues, keeping the enzyme inactive. When
Ca2+ and DAG are present in sufficient concentrations, they bind to the C2 and C1 domain,
respectively, and recruit PKC to the membrane. This interaction with the membrane results in
release of the pseudosubstrate from the catalytic site and activation of the enzyme. In order for
these allosteric interactions to occur, however, PKC must first be properly folded and in the correct
conformation permissive for catalytic action. This is contingent upon phosphorylation of the catalytic
region, discussed below.

Catalytic[edit]
The catalytic region or kinase core of the PKC allows for different functions to be
processed; PKB (also known as Akt) and PKC kinases contains approximately 40% amino acid
sequence similarity. This similarity increases to ~ 70% across PKCs and even higher when
comparing within classes. For example, the two atypical PKC isoforms, and /, are 84% identical
(Selbie et al., 1993). Of the over-30 protein kinase structures whose crystal structure has been
revealed, all have the same basic organization. They are a bilobal structure with a sheet
comprising the N-terminal lobe and an helix constituting the C-terminal lobe. Both the ATP- and
substrate-binding sites are located in the cleft formed by these two lobes. This is also where the
pseudosubstrate domain of the regulatory region binds.[context needed]
Another feature of the PKC catalytic region that is essential to the viability of the kinase is its
phosphorylation. The conventional and novel PKCs have three phosphorylation sites, termed: the
activation loop, the turn motif, and the hydrophobic motif. The atypical PKCs are phosphorylated
only on the activation loop and the turn motif. Phosphorylation of the hydrophobic motif is rendered
unnecessary by the presence of a glutamic acid in place of a serine, which, as a negative charge,
acts similar in manner to a phosphorylated residue. These phosphorylation events are essential for
the activity of the enzyme, and 3-phosphoinositide-dependent protein kinase-1 (PDK1) is the
upstream kinase responsible for initiating the process by transphosphorylation of the activation loop.
[4]

The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it
contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are,
e.g., MARCKS proteins, MAP kinase, transcription factor inhibitor IB, the vitamin
D3 receptor VDR, Raf kinase, calpain, and the epidermal growth factor receptor.

Activation[edit]
Upon activation, protein kinase C enzymes are translocated to the plasma membrane by RACK
proteins (membrane-bound receptor for activated protein kinase C proteins). The protein kinase C
enzymes are known for their long-term activation: They remain activated after the original activation
signal or the Ca2+-wave is gone. It is presumed that this is achieved by the production of
diacylglycerol from phosphatidylinositol by a phospholipase; fatty acids may also play a role in longterm activation.

Function[edit]

A multiplicity of functions have been ascribed to PKC. Recurring themes are that PKC is involved in
receptor desensitization, in modulating membrane structure events, in regulating transcription, in
mediating immune responses, in regulating cell growth, and in learning and memory. These
functions are achieved by PKC-mediated phosphorylation of other proteins. However, the substrate
proteins present for phosphorylation vary, since protein expression is different between different
kinds of cells. Thus, effects of PKC are cell-type-specific:

Cell type

smooth muscle cell

(gastrointestinal
tractsphincters)

Organ/system

Activators
ligands --> Gq-GPCRs

digestive system

prostaglandin
F2[5] -->

Effects

contraction

thromboxanes[5]

smooth muscle cells in:

iris dilator
muscle (sensory
system)

urethral
sphincter (urinary
system)

uterus (reproduc
tive system)

arrector pili
muscles (integument
ary system)

ureter (urinary
system)

urinary
bladder (urinary
system)[6][7]

Various

sensory system

acetylcholine --> M3
receptor

contraction

adrenergic
agonists --> 1
receptor

contraction

smooth muscle cells in:

iris constrictor
muscle

ciliary muscle

smooth muscle cell

(vascular)

circulatory
system

5-HT --> 5HT2A receptor

adrenergic

vasoconstriction[8][9]

Cell type

Organ/system

Activators
ligands --> Gq-GPCRs

Effects

agonists --> 1
receptor
smooth muscle cell
(seminal tract[10])

smooth muscle cell (GI

tract)

smooth muscle cell

(bronchi)

proximal convoluted
tubule cell

neurons in autonomic
ganglia

neurons in CNS

reproductive
system

adrenergic
agonists --> 1
receptor

5-HT --> 5HT2A or 5-HT2B

receptor[8]

digestive system

respiratory
system

ejaculation

acetylcholine (A
Ch) --> M3 receptor

5-HT --> 5HT2A receptor

adrenergic
agonists -->
receptor

acetylcholine -> M3[12] and M1

receptor[13]

angiotensin II -> AT1 receptor

stimulate NHE3 --> H+ secretion

& Na+reabsorption[14]

adrenergic
agonists --> 1
receptor

stimulate basolateral Na-K

ATPase --> Na+reabsorption[14]

bronchoconstriction[8]

kidney

nervous system

contraction[11]

acetylcholine --> M1
receptor

5-HT --> 5HT2A receptor

acetylcholine -> M1 receptor

nervous system

EPSP

neuronal excitation (5-HT)[8]

memory? (acetylcholine)[15]

platelets

circulatory
system

5-HT --> 5-HT2A

receptor[8]

aggregation[8]

ependymal cells (choroid

plexus)

ventricular
system

5-HT --> 5-HT2C

receptor[8]

cerebrospinal fluid secretion[8]

Cell type

heart muscle

serous cells (salivary

gland)

Organ/system

Activators
ligands --> Gq-GPCRs

circulatory
system

adrenergic
agonists --> 1
receptor

acetylcholine -> M1 and M3

receptors

digestive system

adrenergic
agonists --> 1
receptor

Effects

positive ionotropic effect[6]

secretion[6]
increase
salivary potassium levels.

serous cells (lacrimal

gland)

digestive system

acetylcholine -> M3 receptor

adipocyte

digestive
system/endocrine
system

adrenergic
agonists --> 3
receptor

glycogenolysis and gluconeogen

esis[6]

hepatocyte

digestive system

adrenergic
agonists --> 1
receptor

glycogenolysis and gluconeogen

esis[6]

sweat gland cells

integumentary
system

adrenergic
agonists --> 2
receptor

parietal cells

digestive system

acetylcholine --> M1
receptors[13]

secretion[9]

secretion[6]

gastric acid secretion

Pathology[edit]
Protein kinase C, activated by tumor promoter phorbol ester, may phosphorylate potent activators of
transcription, and thus lead to increased expression of oncogenes, promoting cancer progression,
[16]
or interfere with other phenomena.

Inhibitors[edit]
Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic
nephropathy.[17] The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia
peplus, is FDA-approved for the treatment of actinic keratosis.[18][19]

See also[edit]

Serine/threonine-specific protein kinase

Signal transduction

Yasutomi Nishizuka

References[edit]
1.

Jump up^ Wilson, C.H., Ali, E.S., Scrimgeour, N., Martin, A.M., Hua, J., Tallis, G.A., Rychkov, G.Y., and
Barritt, G.J. (2015). Steatosis inhibits liver cell store-operated Ca(2)(+) entry and reduces ER Ca(2)(+) through a
protein kinase C-dependent mechanism. Biochem J 466, 379-390. http://www.ncbi.nlm.nih.gov/pubmed/?
term=Eunus+S+Ali

2.

Jump up^ Mellor H, Parker PJ (1998). "The extended protein kinase C superfamily". Biochem. J. 332.
( Pt 2): 28192. PMC 1219479. PMID 9601053.

3.

Jump up^ Nishizuka Y (1995). "Protein kinase C and lipid signaling for sustained cellular
responses" (abstract). FASEB J. 9 (7): 48496. PMID 7737456.

4.

Jump up^ Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR (July 2000). "A 3phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein
kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1".J. Biol. Chem. 275 (27): 20806
13. doi:10.1074/jbc.M000421200. PMID 10764742.

5.

^ Jump up to:a b Biancani P, Harnett KM (2006). "Signal transduction in lower esophageal sphincter
circular muscle, PART 1: Oral cavity, pharynx and esophagus". GI Motility online.doi:10.1038/gimo24.

6.

^ Jump up to:a b c d e f Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table
20:2".Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.

7.

Jump up^ Chou EC, Capello SA, Levin RM, Longhurst PA (2003). "Excitatory 1-adrenergic receptors
predominate over inhibitory -receptors in rabbit dorsal detrusor". J. Urol. 170(6 Pt 1): 2503
7. doi:10.1097/01.ju.0000094184.97133.69. PMID 14634460.

8.

^ Jump up to:a b c d e f g h Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone.ISBN 0-44307145-4. Page 187

9.

^ Jump up to:a b Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-071454. Page 127

10.

Jump up^ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-071454. Page 163

11.

Jump up^ Sanders KM (July 1998). "G protein-coupled receptors in gastrointestinal physiology. IV.
Neural regulation of gastrointestinal smooth muscle". Am. J. Physiol. 275 (1 Pt 1): G17. PMID 9655677.

12.

Jump up^ Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred
(2006). Goodman & Gilman's the pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill.
p. 185. ISBN 0-07-142280-3.

13.
14.

^ Jump up to:a b "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1".

^ Jump up to:a b Walter F., PhD. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch.
Elsevier/Saunders. ISBN 1-4160-2328-3. Page 787

15.

Jump up^ Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier
Churchill Livingstone. p. 139. ISBN 0-443-07145-4.

16.

Jump up^ Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK (March 2009)."Phosphorylation

of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of
Transcription". J. Biol. Chem. 284 (13): 856781.doi:10.1074/jbc.M808719200. PMC 2659215. PMID 19176525.

17.

Jump up^ Anderson PW, McGill JB, Tuttle KR (September 2007). "Protein kinase C beta inhibition: the
promise for treatment of diabetic nephropathy". Curr. Opin. Nephrol. Hypertens. 16 (5): 397
402. doi:10.1097/MNH.0b013e3281ead025. PMID 17693752.

18.

Jump up^ Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM (2009). "PEP005 (ingenol
mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehiclecontrolled, multicentre, phase IIa study". THE AUSTRALASIAN JOURNAL OF DERMATOLOGY 50 (1): 16
22. doi:10.1111/j.1440-0960.2008.00497.x. PMID 19178487.

19.

Jump up^ "FDA Approves Picato (ingenol mebutate) Gel, the First and Only Topical Actinic Keratosis
(AK) Therapy With 2 or 3 Consecutive Days of Once-Daily Dosing".eMedicine. Yahoo! Finance. January 25, 2012.
Retrieved 2012-02-14.