Protein kinase C alpha (PKCα) is an
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 ...
that in humans is encoded by the ''PRKCA''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
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 t ...
(PKC) is a family of
serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for
phorbol esters
Phorbol esters are a class of chemical compounds found in a variety of plants, particularly in the families Euphorbiaceae and Thymelaeaceae. Chemically, they are ester derivatives of the tetracyclic diterpenoid phorbol.
Biological activity
Prote ...
, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been reported to play roles in many different cellular processes, such as
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as Cell_junction, cell junc ...
, cell transformation,
cell cycle checkpoint
Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, wi ...
, and cell volume control. Knockout studies in mice suggest that this kinase may be a fundamental regulator of
cardiac contractility
Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. The ability to produce changes in force during ...
and Ca
2+ handling in myocytes.
Protein kinase C-alpha (PKC-α) is a specific member of the
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 ...
family. These enzymes are characterized by their ability to add a phosphate group to other proteins, thus changing their function. PKC-α has been widely studied in the tissues of many organisms including drosophila, xenopus, cow, dog, chicken, human, monkey, mouse, pig, and rabbit. Many studies are currently being conducted investigating the structure, function, and regulation of this enzyme. The most recent investigations concerning this enzyme include its general regulation, hepatic function, and cardiac function.
Regulation
PKC-α is unique in its mode of regulation compared to other
kinases
In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
within this family. In general, the
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 ...
family is regulated by
allosteric
In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...
regulation, the binding of a modulating molecule that effects a conformational change in the enzyme and thus a change in the enzyme's activity. The primary mode of PKC-α's regulation, however, involves its interaction with the cell membrane, not direct interaction with specific molecules.
The cell membrane consists of
phospholipids
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 typi ...
. At warmer temperatures, phospholipids exist in a more fluid state as a result of increased intramolecular motion. The more fluid the cell membrane, the greater PKC-α's activity. At cooler temperatures, phospholipids are found in a solid state with constricted motion. As phospholipids become stationary, they assume a particular orientation within the membrane. Phospholipids that solidify at an irregular or angled orientation with respect to the membrane, can reduce PKC-α's activity.
[
The composition of the cell membrane can also affect PKC-α's function. The presence of calcium ions, magnesium ions, and ]diacylglycerols
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are n ...
(DAGs) are the most important because they influence 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 ...
domain of the membrane. Varying concentrations of these three components constitute a longer or shorter length of 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 ...
domain. Membranes with long hydrophobic domains result in decreased activity because it is harder for PKC-α to insert into the membrane. At low concentrations, the hydrophobic domain is shorter allowing PKC-α to readily insert into the membrane and its activity increases.[
]
Secondary structure
Using infrared spectroscopy
Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) is the measurement of the interaction of infrared radiation with matter by absorption, emission, or reflection. It is used to study and identify chemical substances or functio ...
techniques, researchers have demonstrated that the secondary structure of PKC alpha consists of around 44% beta sheets and nearly 22% alpha helices at 20 °C. Upon addition of calcium ions
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
, a slight increase in beta sheets
The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...
to 48% was observed. Additional ligands
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
normally associated with PKC alpha, such as PMA, ATP, and phospholipids had no effect on secondary structure.[
The structure of PKC alpha was better preserved during denaturation of the enzyme at 75 °C in the presence of calcium ]ions
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
than in their absence. In one study, beta sheet
The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...
composition only decreased by 13% with calcium ions present compared to 19% when absent.[
]
Role
Epithelium
Another field of research has indicated that PKC-α plays a vital role in epithelial
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
tissue, the tissue that covers all external and internal surfaces of the body. Specifically, PKC-α is involved in altering the function of tight junctions
Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes between epithelial cells, sealing and preventing leakage of solutes and water. They also play a ...
. Tight junctions exist at the meeting point between two cells. Here, tight junctions fuse together to form an impermeable barrier to not only large molecules such as proteins, but also smaller molecules like water. This prevents foreign molecules from entering the cell and helps regulate the internal environment of the cell. Cells infected with certain types of epithelial cancer exhibit increased PKC-α activity. This is a result of a change in the shape of the cell membrane, particularly in the areas where tight junctions exists. With greater activity of PKC-α, the tight junctions lose their ability to form a tight barrier. This causes an increased leakiness of the tight junctions and thus movement of molecules into the cells. In intestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
areas, luminal growth factors are able to enter the cell and increase the rate of cell growth. This is thought to be a promotional event that may prolong certain epithelial cancers.
Liver
Much of the research of PKC alpha pertaining to its role in liver tissue involves the effects of bile acids on the phosphorylation mechanism of the PKC family of proteins. Past research has affirmed that the bile acid CDCA inhibits the healthy glucagon response through a phosphorylation-related sequence. In related studies further testing the effects of CDCA on hepatocytes, CDCA was shown to have induced PKC translocation to the plasma membrane. PKC alpha was favored in this process over PKC delta. The implications of this finding are that increased interaction between the glucagon receptor and PKC alpha could occur.
Heart
PKC alpha is one of the lesser studied proteins of the PKC family because it is not highly regulated in the serious medical condition known as acute myocardial ischemia
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
, which results from a lack of blood supply to the myocardium
Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
(heart muscle tissue). Recent research into the role of PKC alpha in cardiac tissue has indicated that it has an important role in stimulating hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
. This was demonstrated by the ability of agonist-mediated hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
to be stopped only as a result of the inhibition of PKC alpha in an experiment in situ. However, in further in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
research using mice, the transgenic
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
overexpression of PKC alpha showed no effect on cardiac growth, and the inhibition of PKC alpha showed no effect on hypertrophic
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
response to increased cardiac pressure. On the contrary, research has shown that removing PKC alpha altogether improved the hearts ability to contract.
In summary, research is pointing in the direction that PKC alpha's role in cardiac tissue has more impact as a regulator of contractility than of hypertrophy
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
. In another study, the binding peptides, RACK and others derived from PKC beta, were expressed in mouse hearts. The genetic code for these proteins
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, re ...
are similar to those of all isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of the PKC family (alpha, beta, and gamma). As such, RACK and other proteins
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, re ...
can regulate the expression of all PKC family proteins. In this particular study, however, only PKC alpha was affected. Again, overexpression caused decreased contractile performance, whereas inhibition saw increased performance.[
]
Memory and PTSD
The scientists led by neuroscientist Dominique de Quervain of the University of Basel in Switzerland used memory tests and DNA studies to conclude that people who carried a particular DNA signature in at least one copy of a gene that encodes protein kinase C alpha had stronger memory than their peers; and brain scans of people with the genetic signature show stronger brain activation in parts of the prefrontal cortex compared with those who lacked the genetic feature. The team looked at the Rwandan refugees who had survived the 1994 genocide and found that the risk of PTSD in the refugees with strong memory signature is twice of that in the refugees without the genetic signature.
[
*]
Cell membrane
PKC-α shows important regulation of phospholipase D
Phospholipase D (PLD) (EC 3.1.4.4; also known as lipophosphodiesterase II, lecithinase D, choline phosphatase; systematic name: phosphatidylcholine phosphatidohydrolase) is an anesthetic-sensitive and mechanosensitive enzyme of the phospholipa ...
. Phospholipase D is located on the plasma membrane and is responsible for hydrolyzing phosphatidylcholine to phosphatidic acid and choline
Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...
. Research has indicated that phospholipase D may play roles in tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...
by altering cellular events such as invasion and migration. Point mutations at particular phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
residues have shown to inhibit PKC-α's ability to activate phospholipase D. Current research is being conducted investigating PKC-α's inhibitory affects. Researchers hope to learn how to exploit PKC-α's ability to turn down phospholipase D's activity and use this function to create anti-cancer drugs.
Another breakthrough branch of research concerning PKC-α concerns its role in erythrocyte (red blood cell) development. Currently, researchers understand that PKC-α is correlated with the differentiation of erythroid progenitor cells in bone marrow. These undifferentiated cells give rise to the mass of red blood cells present in blood. Future research endeavors seek to find whether it is activation or inhibition of PKC-α which affects the development of erythrocytes.[ By answering this question, scientists hope to gain insight into various types of hematologic diseases such as aplastic anemia and leukemia.
]
Pathology
Increased activation of PKCα is associated with the growth and invasion of cancers. High levels of PKCα are linked to malignant
Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.
A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
brain cancer. Moreover, a high proliferation rate of glioma
A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are malignant but some are extremely slow to develop. Gliomas comprise about 30% of all brain and central nervous system tumors and 80% of ...
tumor cells is the result of overexpression of isozyme
In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...
PKCα.
Interactions
PKC alpha has been shown to interact with:
* C1QBP
Complement component 1 Q subcomponent-binding protein, mitochondrial is a protein that in humans is encoded by the ''C1QBP'' gene.
The human complement subcomponent C1q associates with C1r and C1s in order to yield the first component of the seru ...
,
* CD29
Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ''ITGB1'' gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen ...
,
* EGFR,
* FSCN1
Fascin is a protein that in humans is encoded by the ''FSCN1'' gene.
Interactions
FSCN1 has been shown to Protein-protein interaction, interact with Low affinity nerve growth factor receptor and PKC alpha.
References
Further reading , and
* OGG1
8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the ''OGG1'' gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species.
Function
OGG1 is th ...
.
References
Further reading
*
*
*
{{DEFAULTSORT:Pkc Alpha
Protein kinases
EC 2.7.11