In
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 enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s through the
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
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 − for ...
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
Calcium is a chemical element with the 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 ...
ions (Ca
2+). 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 series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
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 and ...
, 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
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...
α, β
I, β
II, and γ. These require Ca
2+, 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 Ca
2+ for activation. Thus, conventional and novel PKCs are activated through the same
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathway as
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
. On the other hand, atypical (a)PKCs (including
protein kinase Mζ
Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the ''PRKCZ'' gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ ...
and ι / λ isoforms) require neither Ca
2+ 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
Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contains ...
.
[ ] The broader PKC family is ancient and can be found back in
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
, which means that the PKC family was present in the
last common ancestor of
opisthokonts.
Human isozymes
*conventional - require DAG, Ca
2+, and phospholipid for activation
**
PKC-α ()
**
PKC-β1 ()
**
PKC-β2 ()
**
PKC-γ ()
* novel - require DAG but not Ca
2+ for activation
**
PKC-δ ()
**
PKC-ε ()
**
PKC-η ()
**
PKC-θ ()
* atypical - require neither Ca
2+ nor DAG for activation (require
phosphatidyl serine
Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via ap ...
)
**
PKC-ι ()
**
PKC-ζ ()
* related PKD
**
PKD1 ()
**
PKD2
Polycystin-2 is a protein that in humans is encoded by the ''PKD2'' gene.
This gene encodes a member of the polycystin protein family, called TRPP2, previously known as polycystin-2, PC2 or APKD2. TRPP2 contains multiple transmembrane domains, ...
()
**
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
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate ( binding site) ...
) tethered together by a
hinge region. The catalytic region is highly conserved among the different
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s, as well as, to a lesser degree, among the catalytic region of other
serine/threonine kinases
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...
. 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 the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pattern ...
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 Ca
2+ sensor and is present in both conventional and novel isoforms, but functional as a Ca
2+ 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 Ca
2+ 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 PKB is a three-letter abbreviation that may refer to:
* Państwowy Korpus Bezpieczeństwa, WWII Polish underground police
* Patients Know Best, a tool for allowing the patient to share medical records with clinicians
* National Awakening Party ('' ...
(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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, ...
motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif.
Phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
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.
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 D
Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...
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 for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor re ...
.
Activation
Upon activation, protein kinase C enzymes are translocated to the plasma membrane by
RACK protein
Receptor for activated C kinase 1 (RACK1), also known as guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), is a 35 kDa protein that in humans is encoded by the RACK1 gene.
Function
RACK1 was originally isolated and identified ...
s (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 Ca
2+-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
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. Interestingly, this process is disrupted in
microgravity
The term micro-g environment (also μg, often referred to by the term microgravity) is more or less synonymous with the terms '' weightlessness'' and ''zero-g'', but emphasising that g-forces are never exactly zero—just very small (on the ...
, which causes
immunodeficiency
Immunodeficiency, also known as immunocompromisation, 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 a ...
of
astronauts
An astronaut (from the Ancient Greek (), meaning 'star', and (), meaning 'sailor') is a person trained, equipped, and deployed by a human spaceflight program to serve as a commander or crew member aboard a spacecraft. Although generally r ...
.
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. 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.
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.
Activators
The Protein kinase C activator
ingenol mebutate, derived from the plant ''
Euphorbia peplus
''Euphorbia peplus'' (petty spurge, radium weed, cancer weed, or milkweed), is a species of ''Euphorbia'', native to most of Europe, northern Africa and western Asia, where it typically grows in cultivated arable land, gardens and other disturb ...
'', is FDA-approved for the treatment of
actinic keratosis
Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Actinic k ...
.
Bryostatin 1 can act as a PKCe activator and as of 2016 is being investigated for
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
.
Amended FDA Protocol Submitted for Phase 2b Trial of Advanced Alzheimer’s Therapy. Aug 2016
/ref>
12-O-Tetradecanoylphorbol-13-acetate
12-''O''-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent tumor promoter often employed i ...
(PMA or TPA) is a diacylglycerol mimic that can activate the classical PKCs. It is often used together with ionomycin
Ionomycin is an ionophore and an antibiotic that binds calcium ions (Ca2+) in a ratio 1:1. It is produced by the bacterium '' Streptomyces conglobatus''. It binds also other divalent cations like magnesium and cadmium, but binds Ca2+ preferably.
I ...
which provides the calcium-dependent signals needed for activation of some PKCs.
See also
* Serine/threonine-specific protein kinase
* Signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
* Yasutomi Nishizuka, discovered protein kinase C
* Ccdc60
References
External links
*
*
{{DEFAULTSORT:Protein Kinase C
EC 2.7.11
Protein kinases