Protein kinase C

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]

Protein kinase C
Identifiers
EC no.2.7.11.13
CAS no.141436-78-4
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
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 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

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 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 ejaculation
smooth muscle cell (GI tract)digestive system
smooth muscle cell (bronchi)respiratory system bronchoconstriction[12]: 187 
proximal convoluted tubule cellkidney
  • stimulate NHE3 → H+ secretion & Na+ reabsorption[17]
  • stimulate basolateral Na-K ATPase → Na+ reabsorption[17]
neurons in autonomic ganglianervous systemacetylcholine → M1 receptorEPSP
neurons in CNSnervous system
  • neuronal excitation (5-HT)[12][18]: 187 
  • memory (glutamate)[19]
plateletscirculatory system5-HT → 5-HT2A receptor[12]: 187 aggregation[12]: 187 
ependymal cells (choroid plexus)ventricular system5-HT → 5-HT2C receptor[12]: 187 ↑ cerebrospinal fluid secretion[12]: 187 
heart musclecirculatory system positive ionotropic effect[10]
serous cells (salivary gland)digestive system
serous cells (lacrimal gland)digestive system
  • ↑ secretion[12]: 127 
adipocytedigestive system/endocrine system
hepatocytedigestive system
sweat gland cellsintegumentary system
parietal cellsdigestive systemacetylcholine → M3 receptors[20]↑ gastric acid secretion
lymphocyteimmune system
myelocyteimmune system
  • C-type lectin receptors (CLR) (Dectin 1, Mincle)
  • CARD9/BCL10/MALT1 complex → NF-κB
  • innate immune system

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
  • Serine/threonine-specific protein kinase
  • Signal transduction
  • Yasutomi Nishizuka, discovered protein kinase C
  • Ccdc60

References
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  2. Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (2016). "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. doi:10.1016/j.bbamcr.2016.05.006. PMID 27178543.
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  29. Amended FDA Protocol Submitted for Phase 2b Trial of Advanced Alzheimer’s Therapy. Aug 2016
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