Biology:Protein kinase C

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Short description: Family of enzymes
Protein kinase C
Identifiers
EC number2.7.11.13
CAS number141436-78-4
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Protein kinase C terminal domain
Identifiers
SymbolPkinase_C
PfamPF00433
InterProIPR017892

In cell biology, Protein kinase C, commonly abbreviated to 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, or a member of this family. 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.[2]

In biochemistry, the PKC family consists of fifteen isozymes in humans.[3] They are divided into three subfamilies, based on their second messenger requirements: conventional (or classical), novel, and atypical.[4] 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. The different classes of PKCs found in jawed vertebrates originate from 5 ancestral PKC family members (PKN, aPKC, cPKC, nPKCE, nPKCD) that expanded due to genome duplication.[5] The broader PKC family is ancient and can be found back in fungi, which means that the PKC family was present in the last common ancestor of opisthokonts.

Human isozymes

Structure

Main page: Biology:Protein structure

The structure of all PKCs consists of a regulatory domain and a catalytic domain (Active site) 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-terminus 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-binding protein (ATP)- and the substrate-binding sites are located in the cleft formed by these two terminal 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 (PDPK1) is the upstream kinase responsible for initiating the process by transphosphorylation of the activation loop.[6]

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. A critical part of PKC activation is translocation to the cell membrane. Interestingly, this process is disrupted in microgravity, which causes immunodeficiency of astronauts.[7]

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. PKC plays an important role in the immune system through phosphorylation of CARD-CC family proteins and subsequent NF-κB activation.[8] 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
  • adrenergic agonists → α1 receptor
 contraction
smooth muscle cells in: sensory system acetylcholine → M3 receptor contraction
smooth muscle cell (vascular) circulatory system
smooth muscle cell (seminal tract)[12]:163[13] reproductive system
  • adrenergic agonists → α1 receptor
 ejaculation
smooth muscle cell (GI tract) digestive system
smooth muscle cell (bronchi) respiratory system bronchoconstriction[12]:187
proximal convoluted tubule cell kidney
  • angiotensin II → AT1 receptor
  • adrenergic agonists → α1 receptor
  • stimulate NHE3 → H+ secretion & Na+ reabsorption[17]
  • stimulate basolateral Na-K ATPase → Na+ reabsorption[17]
neurons in autonomic ganglia nervous system acetylcholine → M1 receptor EPSP
neurons in CNS nervous system
  • neuronal excitation (5-HT)[12][18]:187
  • memory (glutamate)[19]
platelets circulatory system 5-HT → 5-HT2A receptor[12]:187 aggregation[12]:187
ependymal cells (choroid plexus) ventricular system 5-HT → 5-HT2C receptor[12]:187 ↑ cerebrospinal fluid secretion[12]:187
heart muscle circulatory system
  • adrenergic agonists → β1 receptor
 positive ionotropic effect[10]
serous cells (salivary gland) digestive system
  • acetylcholine → M1 and M3 receptors
  • adrenergic agonists → β1 receptor
serous cells (lacrimal gland) digestive system
  • ↑ secretion[12]:127
adipocyte digestive system/endocrine system
hepatocyte digestive system
  • adrenergic agonists → α1 receptor
sweat gland cells integumentary system
  • adrenergic agonists → β2 receptor
parietal cells digestive system acetylcholine → M3 receptors[20] ↑ gastric acid secretion
lymphocyte immune system
myelocyte immune system
  • C-type lectin receptors (CLR) (Dectin 1, Mincle)

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,[21] or interfere with other phenomena. Prolonged exposure to phorbol ester, however, promotes the down-regulation of Protein kinase C. Loss-of-function mutations [22] and low PKC protein levels[23] are prevalent in cancer, supporting a general tumor-suppressive role for Protein kinase C.

Protein kinase C enzymes are important mediators of vascular permeability and have been implicated in various vascular diseases including disorders associated with hyperglycemia in diabetes mellitus, as well as endothelial injury and tissue damage related to cigarette smoke. Low-level PKC activation is sufficient to reverse cell chirality through phosphatidylinositol 3-kinase/AKT signaling and alters junctional protein organization between cells with opposite chirality, leading to an unexpected substantial change in endothelial permeability, which often leads to inflammation and disease.[24]

Inhibitors

Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic nephropathy.[25]

Chelerythrine is a natural selective PKC inhibitor. Other naturally occurring PKCIs are miyabenol C, myricitrin, gossypol.

Other PKCIs : Verbascoside, BIM-1, Ro31-8220.

Bryostatin 1 can act as a PKC inhibitor; It was investigated for cancer.

Tamoxifen is a PKC inhibitor.[26]

Activators

The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia peplus, is FDA-approved for the treatment of actinic keratosis.[27][28]

Bryostatin 1 can act as a PKCe activator and as of 2016 is being investigated for Alzheimer's disease.[29]

12-O-Tetradecanoylphorbol-13-acetate (PMA or TPA) is a diacylglycerol mimic that can activate the classical PKCs. It is often used together with ionomycin which provides the calcium-dependent signals needed for activation of some PKCs.

See also

References

  1. ↑ "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. 2015. doi:10.1042/BJ20140881. PMID 25422863. 
  2. ↑ "The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863 (9): 2135–46. 2016. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543. 
  3. ↑ "The extended protein kinase C superfamily". The Biochemical Journal. 332 332 (Pt 2): 281–92. Jun 1998. doi:10.1042/bj3320281. PMID 9601053. 
  4. ↑ "Protein kinase C and lipid signaling for sustained cellular responses". FASEB Journal 9 (7): 484–96. Apr 1995. doi:10.1096/fasebj.9.7.7737456. PMID 7737456. 
  5. ↑ Garcia-Concejo A, Larhammar D (2021). "Protein kinase C family evolution in jawed vertebrates.". Dev Biol 479: 77–90. doi:10.1016/j.ydbio.2021.07.013. PMID 34329618. 
  6. ↑ "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. Jul 2000. doi:10.1074/jbc.M000421200. PMID 10764742. 
  7. ↑ Hauschild, Swantje; Tauber, Svantje; Lauber, Beatrice; Thiel, Cora S.; Layer, Liliana E.; Ullrich, Oliver (2014-11-01). "T cell regulation in microgravity – The current knowledge from in vitro experiments conducted in space, parabolic flights and ground-based facilities". Acta Astronautica 104 (1): 365–377. doi:10.1016/j.actaastro.2014.05.019. ISSN 0094-5765. Bibcode: 2014AcAau.104..365H. 
  8. ↑ Staal, Jens; Driege, Yasmine; Haegman, Mira; Kreike, Marja; Iliaki, Styliani; Vanneste, Domien; Lork, Marie; Afonina, Inna S. et al. (2020-08-13). "Defining the combinatorial space of PKC::CARD-CC signal transduction nodes". The FEBS Journal 288 (5): 1630–1647. doi:10.1111/febs.15522. ISSN 1742-4658. PMID 32790937. https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.15522. 
  9. ↑ 9.0 9.1 "Signal transduction in lower esophageal sphincter circular muscle, PART 1: Oral cavity, pharynx and esophagus". GI Motility Online. 2006. doi:10.1038/gimo24. http://www.nature.com/gimo/contents/pt1/full/gimo24.html. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (Third ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7. 
  11. ↑ "Excitatory alpha1-adrenergic receptors predominate over inhibitory beta-receptors in rabbit dorsal detrusor". The Journal of Urology 170 (6 Pt 1): 2503–7. Dec 2003. doi:10.1097/01.ju.0000094184.97133.69. PMID 14634460. 
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 Rang, HP; Dale, MM; Ritter, JM; Moore, PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. ISBN 978-0-443-07145-4. 
  13. ↑ Koslov, David Stewart; Andersson, Karl-Erik (2013-01-01). "Physiological and pharmacological aspects of the vas deferens—an update". Frontiers in Pharmacology 4: 101. doi:10.3389/fphar.2013.00101. PMID 23986701. 
  14. ↑ "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. Jul 1998. doi:10.1152/ajpgi.1998.275.1.G1. PMID 9655677. 
  15. ↑ Parker, Keith; Brunton, Laurence; 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 978-0-07-142280-2. 
  16. ↑ "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1128. 
  17. ↑ 17.0 17.1 Walter F. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 978-1-4160-2328-9.  Page 787
  18. ↑ "Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning". Proceedings of the National Academy of Sciences of the United States of America 113 (10): E1382–91. 2016. doi:10.1073/pnas.1525586113. PMID 26903620. Bibcode: 2016PNAS..113E1382B. 
  19. ↑ "Atypical PKCs in memory maintenance: the roles of feedback and redundancy". Learning & Memory 22 (7): 344–53. 2015. doi:10.1101/lm.038844.115. PMID 26077687. 
  20. ↑ Boron, Walter F.. Medical Physiology. 
  21. ↑ "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. March 2009. doi:10.1074/jbc.M808719200. PMID 19176525. 
  22. ↑ "Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor". Cell 160 (3): 489–502. January 2015. doi:10.1016/j.cell.2015.01.001. PMID 25619690. 
  23. ↑ "Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer". Molecular Cell 74 (2): 378–392.e5. March 2019. doi:10.1016/j.molcel.2019.02.018. PMID 30904392. 
  24. ↑ "Cell chirality regulates intercellular junctions and endothelial permeability". Science Advances 4 (10): eaat2111. 24 October 2018. doi:10.1126/sciadv.aat2111. PMID 30397640. Bibcode: 2018SciA....4.2111F. 
  25. ↑ "Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy". Current Opinion in Nephrology and Hypertension 16 (5): 397–402. Sep 2007. doi:10.1097/MNH.0b013e3281ead025. PMID 17693752. 
  26. ↑ Zarate, Carlos A.; Manji, Husseini K. (2009). "Protein Kinase C Inhibitors: Rationale for Use and Potential in the Treatment of Bipolar Disorder". CNS Drugs 23 (7): 569–582. doi:10.2165/00023210-200923070-00003. ISSN 1172-7047. PMID 19552485. 
  27. ↑ "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. Feb 2009. doi:10.1111/j.1440-0960.2008.00497.x. PMID 19178487. 
  28. ↑ "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. https://finance.yahoo.com/news/fda-approves-picato-ingenol-mebutate-130200825.html. 
  29. ↑ Amended FDA Protocol Submitted for Phase 2b Trial of Advanced Alzheimer’s Therapy. Aug 2016

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