Protein kinase C

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
Protein kinase C terminal domain
Identifiers
Symbol Pkinase_C
Pfam PF00433
InterPro IPR017892

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 α, βI, βII, and γ. These require Ca2+, DAG, and a phospholipid such as phosphatidylserine for activation. Novel (n)PKCs include the δ, ε, η, and θ 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 Mζ and ι / λ isoforms) require neither Ca2+ nor diacylglycerol for activation. The term "protein kinase C" usually refers to the entire family of isoforms.

Isozymes

Structure

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

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 non-hydrolysable, 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 Ca2+ 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

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, ζ and ι/λ, 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 β sheet comprising the N-terminal lobe and an α 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.

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 IκB, the vitamin D3 receptor VDR, Raf kinase, calpain, and the epidermal growth factor receptor.

Activation

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 long-term activation.

Function

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 Organ/system Activators
ligands --> Gq-GPCRs		 Effects
smooth muscle cell (gastrointestinal tract sphincters) digestive system contraction
smooth muscle cells in: Various contraction
smooth muscle cells in: sensory system acetylcholine --> M3 receptor contraction
smooth muscle cell (vascular) circulatory system
smooth muscle cell (seminal tract[8]:163 reproductive system ejaculation
smooth muscle cell (GI tract) digestive system
smooth muscle cell (bronchi) respiratory system bronchoconstriction[8]:187
proximal convoluted tubule cell kidney
neurons in autonomic ganglia nervous system acetylcholine --> M1 receptor EPSP
neurons in CNS nervous system
  • neuronal excitation (5-HT)[8]:187
  • memory? (acetylcholine)[8]
platelets circulatory system 5-HT --> 5-HT2A receptor[8]:187 aggregation[8]:187
ependymal cells (choroid plexus) ventricular system 5-HT --> 5-HT2C receptor[8]:187 ↑cerebrospinal fluid secretion[8]:187
heart muscle circulatory system positive ionotropic effect[6]
serous cells (salivary gland) digestive system
serous cells (lacrimal gland) digestive system
  • ↑secretion[8]:127
adipocyte digestive system/endocrine system
hepatocyte digestive system
sweat gland cells integumentary system
  • ↑secretion[6]
parietal cells digestive system acetylcholine --> M1 receptors[11] ↑ gastric acid secretion

Pathology

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,[13] or interfere with other phenomena.

Inhibitors

Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic nephropathy.[14] The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia peplus, is FDA-approved for the treatment of actinic keratosis.[15][16]

See also

References

  1. ↑ Wilson CH, Ali ES, Scrimgeour N, Martin AM, Hua J, Tallis GA, Rychkov GY, Barritt GJ (2015). "Steatosis inhibits liver cell store-operated Ca²⁺ entry and reduces ER Ca²⁺ through a protein kinase C-dependent mechanism". The Biochemical Journal 466 (2): 379–90. doi:10.1042/BJ20140881. PMID 25422863.
  2. ↑ Mellor H, Parker PJ (Jun 1998). "The extended protein kinase C superfamily". The Biochemical Journal. 332 332 (Pt 2): 281–92. doi:10.1042/bj3320281. PMC 1219479. PMID 9601053.
  3. ↑ Nishizuka Y (Apr 1995). "Protein kinase C and lipid signaling for sustained cellular responses" (abstract). FASEB Journal 9 (7): 484–96. PMID 7737456.
  4. ↑ Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR (Jul 2000). "A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1". The Journal of Biological Chemistry 275 (27): 20806–13. doi:10.1074/jbc.M000421200. PMID 10764742.
  5. 1 2 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. 1 2 3 4 5 6 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
  7. ↑ Chou EC, Capello SA, Levin RM, Longhurst PA (Dec 2003). "Excitatory alpha1-adrenergic receptors predominate over inhibitory beta-receptors in rabbit dorsal detrusor". The Journal of Urology 170 (6 Pt 1): 2503–7. doi:10.1097/01.ju.0000094184.97133.69. PMID 14634460.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. ISBN 0-443-07145-4.
  9. ↑ Sanders KM (Jul 1998). "G protein-coupled receptors in gastrointestinal physiology. IV. Neural regulation of gastrointestinal smooth muscle". The American Journal of Physiology 275 (1 Pt 1): G1–7. PMID 9655677.
  10. ↑ 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.
  11. 1 2 "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1".
  12. 1 2 Walter F., PhD. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 787
  13. ↑ Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK (Mar 2009). "Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription". The Journal of Biological Chemistry 284 (13): 8567–81. doi:10.1074/jbc.M808719200. PMC 2659215. PMID 19176525.
  14. ↑ Anderson PW, McGill JB, Tuttle KR (Sep 2007). "Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy". Current Opinion in Nephrology and Hypertension 16 (5): 397–402. doi:10.1097/MNH.0b013e3281ead025. PMID 17693752.
  15. ↑ Siller G, Gebauer K, Welburn P, Katsamas J, Ogbourne SM (Feb 2009). "PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, double-blind, vehicle-controlled, multicentre, phase IIa study". The Australasian Journal of Dermatology 50 (1): 16–22. doi:10.1111/j.1440-0960.2008.00497.x. PMID 19178487.
  16. ↑ "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.

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