Protein kinase C

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For other uses, see PKC (disambiguation).
Protein kinase C
Identifiers
ExPASy
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KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Protein kinase C terminal domain
Identifiers
SymbolPkinase_C
PfamPF00433
InterProIPR017892
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

In

diacylglycerol (DAG) or calcium ions (Ca2+).[1] Hence PKC enzymes play important roles in several signal transduction cascades.[2]

In

opisthokonts
.

Human isozymes

Structure

Main article: Protein structure
For more, see Protein domain and Protein kinase domain.

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

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;

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

PDPK1) is the upstream kinase responsible for initiating the process by transphosphorylation of the activation loop.[6]

The

Raf kinase, calpain, and the epidermal growth factor receptor
.

Activation

Upon activation, protein kinase C enzymes are translocated to the plasma membrane by

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
GPCRs
 Effects
smooth muscle cell (gastrointestinal tract sphincters)
digestive system
 contraction
smooth muscle cells in: Various
  • α1 receptor
 contraction
smooth muscle cells in:
sensory system
M3 receptor
 contraction
smooth muscle cell (vascular) circulatory system
smooth muscle cell (seminal tract)[12]: 163 [13] reproductive system
  • α1 receptor
 ejaculation
smooth muscle cell (GI tract)
digestive system
bronchi
)		 respiratory system bronchoconstriction[12]: 187 
proximal convoluted tubule cell
 kidney
  • AT1 receptor
  • α1 receptor
autonomic ganglia
 nervous system
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
  • β1 receptor
 positive ionotropic effect[10]
serous cells (salivary gland
)
digestive system
  • M3 receptors
  • β1 receptor
serous cells (lacrimal gland
)
digestive system
  • M3 receptor
  • ↑ secretion[12]: 127 
adipocyte
digestive system/endocrine system
hepatocyte
digestive system
  • α1 receptor
sweat gland cells integumentary system
  • β2 receptor
parietal cells
digestive system
M3 receptors[20]
 ↑ gastric acid secretion
lymphocyte immune system
myelocyte immune system
  • C-type lectin receptors (CLR) (
    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]

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. PMID 25422863
    .
  2. PMID 27178543
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  3. PMID 9601053
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  4. S2CID 31065063
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  5. PMID 34329618
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  7. ISSN 0094-5765
    .
  8. S2CID 221123226
    .
  9. ^
    doi:10.1038/gimo24 (inactive 31 January 2024).{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link
    )
  10. ^
    ISBN 978-0-87893-725-7
    .
  11. PMID 14634460
    .
  12. ^
    ISBN 978-0-443-07145-4
    .
  13. PMID 23986701
    .
  14. PMID 9655677
    .
  15. ISBN 978-0-07-142280-2
    .
  16. ^ "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1".
  17. ^
    ISBN 978-1-4160-2328-9
    . Page 787
  18. PMID 26903620
    .
  19. PMID 26077687
    .
  20. ^ Boron, Walter F. Medical Physiology.
  21. PMID 19176525
    .
  22. PMID 25619690
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  23. PMID 30904392
    .
  24. PMID 30397640
    .
  25. S2CID 72887329
    .
  26. PMID 19552485
    .
  27. S2CID 19308099
    .
  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. Archived from the original on February 10, 2012. Retrieved 2012-02-14.
  29. ^ Amended FDA Protocol Submitted for Phase 2b Trial of Advanced Alzheimer’s Therapy. Aug 2016

External links

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