cell biology Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living an ...

, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s that are involved in controlling the function of other

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s through the

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of hydroxyl groups of

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

and

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

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 Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

ions (Ca²⁺). Hence PKC enzymes play important roles in several

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...

cascades. In

biochemistry Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, a ...

, the PKC family consists of fifteen isozymes in humans. They are divided into three subfamilies, based on their second messenger requirements: conventional (or classical), novel, and atypical. Conventional (c)PKCs contain the isoforms α, β_I, β_II, and γ. These require Ca²⁺, DAG, and a

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

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

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. The broader PKC family is ancient and can be found back in

fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

, which means that the PKC family was present in the last common ancestor of opisthokonts.

Human isozymes

*conventional - require DAG, Ca²⁺, and phospholipid for activation ** PKC-α () ** PKC-β1 () ** PKC-β2 () ** PKC-γ () * novel - require DAG but not Ca²⁺ for activation ** PKC-δ () ** PKC-ε () ** PKC-η () ** PKC-θ () * atypical - require neither Ca²⁺ nor DAG for activation (require phosphatidyl serine) ** PKC-ι () ** PKC-ζ () * related PKD **

PKD1 Polycystin 1 (PC1) is a protein that in humans is encoded by the ''PKD1'' gene. Mutations of ''PKD1'' are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by ...

() **

PKD2 Polycystin-2 (PC2) is a protein that in humans is encoded by the ''PKD2'' gene. The gene ''PKD2'' also known as TRPP2, encodes a member of the polycystin protein family, called TRPP, and contains multiple transmembrane domains, and cytoplasmic N- ...

() ** PKD3 () * related PKN ** PK-N1 () ** PK-N2 () ** PK-N3 ()

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 In crystallography, crystal structure is a description of ordered arrangement of atoms, ions, or molecules in a crystalline material. Ordered structures occur from intrinsic nature of constituent particles to form symmetric patterns that repeat ...

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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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 site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

s 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 In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif.

Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of the hydrophobic motif is rendered unnecessary by the presence of a

glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...

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. The

consensus sequence In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated sequence of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It represents the result ...

of protein kinase C enzymes is similar to that of protein kinase A, since it contains

basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...

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 D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...

₃ receptor VDR, Raf kinase, calpain, and the

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...

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). This localization also gives the enzyme access to substrate, an activation mechanism termed substrate 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 a

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *Phospholipase ...

; fatty acids may also play a role in long-term activation. A critical part of PKC activation is translocation to the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Interestingly, this process is disrupted in

microgravity Weightlessness is the complete or near-complete absence of the sensation of weight, i.e., zero apparent weight. It is also termed zero g-force, or zero-g (named after the g-force) or, incorrectly, zero gravity. Weight is a measurement of the fo ...

, which causes

immunodeficiency Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that aff ...

of astronauts.

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. PKC isoforms have been designated "memory kinases," and deficits in PKC signaling in neurons is an early abnormality in the brains of patients with

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

activation. 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:

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, or interfere with other phenomena. Prolonged exposure to phorbol ester, however, promotes the down-regulation of Protein kinase C. Loss-of-function mutations and low PKC protein levels 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.

Inhibitors

Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic nephropathy. Chelerythrine is a natural ''selective'' PKC inhibitor. Other naturally occurring PKCIs are miyabenol C, myricitrin, gossypol. Bryostatin 1 can act as a PKC inhibitor; It was investigated for cancer. Darovasertib is an investigational new drug in efficacy trials in treatment of metastatic uveal melanoma. Other PKCIs include Verbascoside, BIM-1, Ro31-8220, and

Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...

Activators

The Protein kinase C activator ingenol mebutate, derived from the plant '' Euphorbia peplus'', is FDA-approved for the treatment of actinic keratosis. Bryostatin 1 can act as a PKCe activator and as of 2016 is being investigated for

. Amended FDA Protocol Submitted for Phase 2b Trial of Advanced Alzheimer’s Therapy. Aug 2016
/ref> 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.

References

External links

* * {{DEFAULTSORT:Protein Kinase C EC 2.7.11 Protein kinases