Proteinkinase C

Protein kinase C ( PKC short ) is an enzyme family of protein kinases. By the transfer of phosphate on serine or Threoningruppen controls the activity downstream enzymes or factors. Due to this regulatory function of protein kinase C has a central role in cellular signal transduction ( signal transduction). Calcium ions ( Ca2 ), and diacylglycerol phospholipids are required for the activity of PKC. Sphingosine inhibits the other hand, the PKC.

PKC was discovered by the work of Yasutomi Nishizuka and co-workers as phospholipid -dependent kinase, whose activity could be further enhanced by diacylglycerol.

Other important members of the enzyme class of protein kinases, protein kinase A, protein kinase B and protein kinase G.

Structure

Protein kinase C is composed of a N-terminal regulatory (R ) and a catalytic C-terminal domain (C). As also described for protein kinase A, has the regulatory domain to a pseudosubstrate sequence that blocks the active site of the catalytic domain at rest: Instead of a phosphorylated serine residue is an alanine residue present here.

Currently ten isozymes of protein kinase C is known. It has now been cloned from Drosophila and numerous mammals. There are three groups of PKC isoenzymes: the classical PKC ( CPKC ), the new PKC ( nPKC ) and atypical PKC ( aPKC ). Their molecular masses amount to 61-154 kDa. The CPKC isoforms are α, β1, β2 and γ, are among the nPKC isoforms ε, δ, η and θ and aPKC isoforms consist of ζ and λ / τ. In the literature a PKCμ is known, but it is referred to as protein kinase D1.

The CPKC isoforms are activated by the secondary signals Ca2 and diacylglycerol (DAG ), the nPKC isoforms are activated by DAG, and aPKC are against Ca2 - and DAG - independent. In addition, there are other, cellular and isoformabhängige activation and Inaktivierungswege

In PKCλ and PKCτ is the so-called orthotopic enzymes in mice PKCλ is expressed during the same functions are performed by PKCτ in humans.

Function and regulation

Signal transduction

Protein kinase C has a central role in signal transduction. Its activity is controlled by hormones and neurotransmitters, its signal is transmitted via second messengers, called the second messenger. PKC family of enzymes are inactive from the beginning. Instead, they are - depending on the isoenzyme - a complex activation sequence and are brought to the desired site of action, before they are fully catalytically active.

Bond a number of neurotransmitters, growth factors and hormones to their G protein- coupled receptors ( GPCR) mediated through the activation of phospholipase C (PLC ), the release of the second messenger inositol -1 ,4,5- trisphosphate (IP3 ) and diacylglycerol ( DAG) from the membrane component phosphatidylinositol -4 ,5 -bisphosphate ( PIP2 ) ( see illustration). IP3 binds to receptors in the membrane of intracellular calcium store ( endoplasmic reticulum and / or mitochondria) and causes the release of Ca2 . This efflux of calcium ions into the cytosol leads to activation of calcium-dependent protein kinases.

For the function of the protein kinase C Ca2 is required. In addition, the binding to phosphatidylserine, a lipid component of the inner side of the cell membrane, is required. On the resulting in the hydrolysis of PIP2 diacylglycerol, a secondary signal, integrates the peripheral membrane -bound form of PKC which is in equilibrium with the cytosolic form. This PKC is activated and catalyzes the phosphorylation of many target proteins.

Cell proliferation

PKC has importance in the regulation of cellular growth. A malfunction may be involved in the initiation of cancer and in the development of late diabetic complications.

The importance of PKC for cell division and proliferation became apparent when it was realized the effect of the phorbol ester. Phorbol esters, polycyclic alcohol derivatives such as 12-O- tetradecanoylphorbol - 13-acetate (TPA ), are important carcinogens, while not itself initiate tumor formation, but the promote of carcinogenic substances. Phorbol esters activate the enzyme due to their similarity to the natural activator DAG. The resulting mediated activity has long endure, since phorbol esters in contrast to DAG will degrade slowly.

In patients with diabetes mellitus increased blood sugar levels lead to an increase in diacylglycerol concentration in the cell, thus leading to activation of protein kinase C. This promotes the production of extracellular matrix and cytokines, contractility and permeability increases ( permeability ) of blood vessels, increases the cell growth in blood vessels activates the phospholipase A2, and inhibits Na / K -ATPase. This results in vascular damage the retina of the eye, the kidney and the heart. Ruboxistaurin, an inhibitor of protein kinase C, may be able to favorably influence damage to the small blood vessels ( microangiopathy ) in patients with diabetes.

Signaling processes in immune cells

Whether PKC isozymes have a function in signaling processes in immune cells, is the subject of research. May play in the signal of B- or T- cells, the isoenzymes α, β and θ an important role. So to be important for the activation of T cells nPKC - θ. In mice it has been shown that their T cells exhibit severe disturbances in the T- cell mediated activation when one is not nPKC - θ formed with them. However a B -cell function is normal.

Next to the θ - isoenzyme and the α isoform of T cells may be important. Upon activation of T cells, the distribution of PKC - α is increased in the short term. PKC - β is important for the activation of B cells. If you removed the genes for the β1 - β2 and - isoform in mice, an immune deficiency develops. The aPKC - ζ is important for function of the B cells.