Protein kinase C

from Wikipedia, the free encyclopedia
Protein kinase C
Cofactor DAG (conv./nov.); Ca 2+ (conv.)
Isoforms α / βI / βII / γ (conventional); δ / ε / η / θ (novel); Mζ / ι / λ (atypical)
Enzyme classification
EC, category 2.7.11.13 ,  kinase
Response type Phosphorylation
Substrate ATP + protein
Products ADP + phosphoprotein
Occurrence
Parent taxon Chordates

The protein kinase C (short PKC ) is an enzyme family of protein kinases . By transferring phosphate to serine or threonine groups , it controls the activity of downstream enzymes or factors. Due to this regulatory function, protein kinase C plays a central role in cellular signal transmission ( signal transduction ). Calcium ions (Ca 2+ ), phospholipids and diacylglycerin are necessary for PKC to be active. In contrast, sphingosine inhibits the PKC.

The PKC was discovered through the work of Yasutomi Nishizuka and co-workers as a phospholipid-dependent kinase, the activity of which could be increased by diacylglycerol.

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

structure

Protein kinase C consists of a regulatory N-terminal (R) and a catalytic C-terminal domain (C). As also described for protein kinase A, the regulatory domain has a pseudo-substrate sequence that blocks the active center of the catalytic domain in the resting state: Instead of a phosphorylatable serine residue, an alanine residue is present here.

Ten isoenzymes of protein kinase C are currently known. It has since been cloned from Drosophila and numerous mammals . There are three groups of PKC isoenzymes: the classic PKC (cPKC), the new PKC (nPKC) and atypical PKC (aPKC). Their molecular weights are 61 to 154  kDa . The cPKC isoforms include α, β 1 , β 2 and γ, the nPKC isoforms include ε, δ, η and θ and the aPKC isoforms consist of ζ and λ / τ. A PKCμ is also known in the literature, but it is referred to as protein kinase D1.

The cPKC isoforms are activated by the secondary signals Ca 2+ and diacylglycerol (DAG), the nPKC isoforms are only activated by DAG, and aPKC, on the other hand, are Ca 2+ and DAG-independent. In addition, there are other cell- and isoform-dependent activation and inactivation pathways.

PKCλ and PKCτ are the so-called orthotopic enzymes, PKCλ is expressed in mice, while PKCτ performs the same functions in humans.

Function and regulation

Signal transduction

Schematic overview of the activation of protein kinase C. Please see text for details.

Protein kinase C is of central importance in signal transduction. Their activity is controlled by hormones and neurotransmitters , the signal of which is passed on via secondary messenger substances, so-called second messengers . PKC family enzymes are not active from the start. Instead, depending on the isoenzyme, they are subject to a complex activation sequence and are brought to the desired site of action before they are fully catalytically active.

Binding of a number of neurotransmitters, growth factors and hormones to their G-protein-coupled receptors (GPCR) mediates the release of the second messenger inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol via the activation of phospholipase C (PLC) (DAG) from the membrane component phosphatidylinositol-4,5-bisphosphate (PIP 2 ) (see figure). IP 3 binds to receptors in the membrane of intracellular calcium stores ( endoplasmic reticulum and / or mitochondria ) and causes the release of Ca 2+ . This outflow of calcium ions into the cytosol leads to the activation of calcium-dependent protein kinases.

Ca 2+ is required for the function of protein kinase C. It also requires binding to phosphatidylserine , a lipid component of the inner face of the cell membrane . The peripheral-membrane-bound form of PKC, which is in equilibrium with the cytosolic form, binds to the diacylglycerol formed during the hydrolysis of PIP 2 , a secondary signal. This activates PKC and catalyzes the phosphorylation of many target proteins.

Cell proliferation

Structure of TPA, a carcinogenic activator of PKC.

PKC is important in regulating cellular growth. A malfunction can be involved in the triggering of cancer and in the development of diabetic complications.

The importance of PKC for cell division and proliferation became apparent when the phorbol esters were recognized. Phorbol esters, polycyclic alcohol derivatives such as 12-O-tetradecanoylphorbol-13-acetate (TPA), are important carcinogens that do not initiate tumor formation themselves, but promote that of carcinogenic substances. Phorbol esters activate the enzyme due to their similarity to the natural activator DAG. The activity mediated by this lasts for a long time, since phorbol esters, in contrast to DAG, are only broken down slowly.

In patients with diabetes mellitus , increased blood sugar levels lead to an increase in the diacylglycerol concentration in the cell and thus to an activation of protein kinase C. This promotes the production of extracellular matrix and cytokines , increases the contractility and permeability of blood vessels, increases the Cell growth in blood vessels , activates phospholipase A2 and inhibits Na + / K + -ATPase . The result is vascular damage to 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 isoenzymes have a function in signaling processes in immune cells is the subject of research. The isoenzymes α, β and θ may play an important role in the signaling pathway of B or T cells . So nPKC-θ is said to be important for the activation of T cells. In mice it has been shown that their T cells have severe interference with T-cell-mediated activation if they are not produced with nPKC-θ. In contrast, their B-cell function is normal.

In addition to the θ isoenzyme, the α isoenzyme could also be important for T cells. When the T cells are activated, the release of PKC-α is briefly increased. PKC-β is important for the activation of B cells. If the genes for the β 1 and β 2 isoforms are removed from mice , an immunodeficiency develops. The aPKC-ζ is also important for the function of the B cells.

Individual evidence

  1. ↑ Nakamura, S. and Yamamura, H. (2010): Yasutomi Nishizuka: father of protein kinase C . In: J Biochem . 148 (2); 125-130; PMID 20668066 ; PDF (free full text access)
  2. ↑ a b c d Daisuke Kitamura: How the Immune System Recognizes Self and Nonself: Immunoreceptors and Their Signaling . Springer-Verlag GmbH 2007; ISBN 978-4431738831 ; P. 107f.
  3. ^ H. Robert Horton, Laurence A. Moran, K. Gray Scrimgeour, Marc D. Perry, J. David Rawn and Carsten Biele (translators): Biochemie . Pearson Studies; 4th updated edition 2008; ISBN 978-3-8273-7312-0 ; P. 386ff.
  4. ↑ D. Koya, GL King: Protein kinase C activation and the development of diabetic complications. In: Diabetes 47: pp. 859-866.
  5. ^ Gerhard Krauss: Biochemistry of Signal Transduction and Regulation . Wiley-VCH; 2nd, change Edition 2001; ISBN 978-3527303779 ; P. 259
  6. ^ VJ Scott et al. a .: Ruboxistaurin, a Protein Kinase C β Inhibitor, as an Emerging Treatment for Diabetes Microvascular Complications ( Memento of the original of September 28, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Ann Pharmacother . 39: pp. 1693-1699. @1@ 2Template: Webachiv / IABot / www.theannals.com
  7. ↑ Baier, G. (2003): The PKC gene module: molecular biosystematics to resolve its T cell functions . In: Immunol Rev . 192; 64-79; PMID 12670396 ; doi : 10.1034 / j.1600-065X.2003.00018.x
  8. ↑ Baier, G. and Wagner, J. (2009): PKC inhibitors: potential in T cell-dependent immune diseases . In: Curr Opin Cell Biol . 21 (2); 262-267; PMID 19195860 ; doi : 10.1016 / j.ceb.2008.12.008
  9. ↑ Guo, B., Su, TT. and Rawlings, DJ. (2004): Protein kinase C family functions in B-cell activation . In: Curr Opin Immunol . 16 (3); 367-373; PMID 15134787 ; doi : 10.1016 / j.coi.2004.03.012

Web links