| Protein kinase C | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 2.7.11.13 | ||||||||
| CAS no. | 141436-78-4 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
| Protein kinase C terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Pkinase_C | ||||||||
| Pfam | PF00433 | ||||||||
| InterPro | IPR017892 | ||||||||
| |||||||||
Incell biology,protein kinase C, commonly abbreviated toPKC (EC 2.7.11.13), is a family ofprotein kinaseenzymes that are involved in controlling the function of otherproteins through thephosphorylation ofhydroxyl groups ofserine andthreonine 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 ofdiacylglycerol (DAG) orcalcium ions (Ca2+).[1] Hence PKC enzymes play important roles in severalsignal transduction cascades.[2]
Inbiochemistry, the PKC family consists of fifteenisozymes 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 theisoforms α, βI, βII, and γ. These require Ca2+, DAG, and aphospholipid such asphosphatidylserine 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 samesignal transduction pathway asphospholipase C. On the other hand, atypical (a)PKCs (includingprotein 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 injawed vertebrates originate from 5 ancestral PKC family members (PKN, aPKC, cPKC, nPKCE, nPKCD) that expanded due togenome duplication.[5] The broader PKC family is ancient and can be found back infungi, which means that the PKC family was present in thelast common ancestor ofopisthokonts.
The structure of all PKCs consists of a regulatory domain and a catalytic domain (active site) tethered together by ahinge region. The catalytic region is highly conserved among the differentisoforms, as well as, to a lesser degree, among the catalytic region of otherserine/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 thecrystal 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.
The regulatory domain or theamino-terminus of the PKCs contains several shared subregions. TheC1 domain, present in all of the isoforms of PKC has a binding site for DAG as well as non-hydrolysable, non-physiological analogues calledphorbol 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. TheC2 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. Thepseudosubstrate 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.
The catalytic region or kinase core of the PKC allows for different functions to be processed;PKB (also known asAkt) 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 theATP-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: theactivation loop, theturn motif, and thehydrophobic 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 aglutamic 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]
Theconsensus sequence of protein kinase C enzymes is similar to that ofprotein kinase A, since it containsbasic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are, e.g.,MARCKS proteins,MAP kinase, transcription factor inhibitor IκB, thevitamin D3 receptorVDR,Raf kinase,calpain, and theepidermal growth factor receptor.
Upon activation, protein kinase C enzymes are translocated to the plasma membrane byRACK proteins (membrane-bound receptor for activated protein kinase C proteins). This localization also gives the enzyme access to substrate, an activation mechanism termedsubstrate presentation. 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 aphospholipase; fatty acids may also play a role in long-term activation. A critical part of PKC activation is translocation to thecell membrane. Interestingly, this process is disrupted inmicrogravity, which causesimmunodeficiency ofastronauts.[7]
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. PKC isoforms have been designated "memory kinases," and deficits in PKC signaling in neurons is an early abnormality in the brains of patients withAlzheimer's disease.[8] These functions are achieved by PKC-mediated phosphorylation of other proteins. PKC plays an important role in the immune system through phosphorylation ofCARD-CC family proteins and subsequentNF-κB activation.[9] 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:
Protein kinase C, activated by tumor promoterphorbol ester, may phosphorylate potent activators of transcription, and thus lead to increased expression of oncogenes, promoting cancer progression,[22] or interfere with other phenomena. Prolonged exposure to phorbol ester, however, promotes the down-regulation of Protein kinase C. Loss-of-function mutations[23] and low PKC protein levels[24] 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.[25]
Protein kinase C inhibitors, such asruboxistaurin, may potentially be beneficial in peripheraldiabetic nephropathy.[26]
Chelerythrine is a naturalselective PKC inhibitor. Other naturally occurring PKCIs aremiyabenol C,myricitrin,gossypol.
Bryostatin 1 can act as a PKC inhibitor; It was investigated for cancer.
Darovasertib is aninvestigational new drug in efficacy trials in treatment of metastaticuveal melanoma.[27][28]
Other PKCIs includeVerbascoside,BIM-1,Ro31-8220, andTamoxifen.[29]
The Protein kinase C activatoringenol mebutate, derived from the plantEuphorbia peplus, is FDA-approved for the treatment ofactinic keratosis.[30][31]
Bryostatin 1 can act as a PKCe activator and as of 2016 is being investigated forAlzheimer's disease.[32]
12-O-Tetradecanoylphorbol-13-acetate (PMA or TPA) is adiacylglycerol mimic that can activate the classical PKCs. It is often used together withionomycin which provides the calcium-dependent signals needed for activation of some PKCs.
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