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cGMP-dependent protein kinase or Protein Kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell division, and nucleic acid synthesis.
Genes and proteinsEdit
PKG are serine/threonine kinases that are present in a variety of eukaryotes ranging from the unicellular organism Paramecium to humans. Two PKG genes, coding for PKG type I (PKG-I) and type II (PKG-II), have been identified in mammals. The N-terminus of PKG-I is encoded by two alternatively spliced exons that specify for the PKG-Iα and PKG-Iβ isoforms. PKG-Iβ is activated at ~10-fold higher cGMP concentrations than PKG-Iα. The PKG-I and PKG-II are homodimers of two identical subunits (~75 kDa and ~85 kDa, respectively) and share common structural features.
Each subunit is composed of three functional domains:
- (1) an N-terminal domain that mediates homodimerization, suppression of the kinase activity in the absence of cGMP, and interactions with other proteins including protein substrates
- (2) a regulatory domain that contains two non-identical cGMP-binding sites
- (3) a kinase domain that catalyzes the phosphate transfer from ATP to the hydroxyl group of a serine/threonine side chain of the target protein
Binding of cGMP to the regulatory domain induces a conformational change which stops the inhibition of the catalytic core by the N-terminus and allows the phosphorylation of substrate proteins. Whereas PKG-I is predominantly localized in the cytoplasm, PKG-II is anchored to the plasma membrane by N-terminal myristoylation.
In general, PKG-I and PKG-II are expressed in different cell types.
- PKG-I has been detected at high concentrations (above 0.1 µmol/L) in all types of smooth muscle cells (SMCs) including vascular SMCs and in platelets. Lower levels are present in vascular endothelium and cardiomyocytes. The enzyme is also expressed in fibroblasts, certain types of renal cells and leukocytes, and in specific regions of the nervous system, for example in the hippocampus, in cerebellar Purkinje cells, and in dorsal root ganglia. Neurons express either the PKG-Iα or the PKG-Iβ isoform, platelets predominantly Iβ, and both isoforms are present in smooth muscle.
- PKG-II has been detected in renal cells, zona glomerulosa cells of the adrenal cortex, Clara cells in distal airways, intestinal mucosa, pancreatic ducts, parotid and submandibular glands, chondrocytes, and several brain cell nuclei, but not in cardiac and vascular myocytes.
Specifically, in smooth muscle tissue, PKG promotes the opening of calcium-activated potassium channels, leading to cell hyperpolarization and relaxation, and blocks agonist activity of phospholipase C, reducing liberation of stored calcium ions by inositol triphosphate.
Role in cancerEdit
See also Edit
- ↑ Kwon IK, Schoenlein PV, Delk J, Liu K, Thangaraju M, Dulin NO, Ganapathy V, Berger FG, Browning DD (April 2008). Expression of cyclic guanosine monophosphate-dependent protein kinase in metastatic colon carcinoma cells blocks tumor angiogenesis. Cancer 112 (7): 1462–70.
- EC 220.127.116.11
- Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System
- MeSH cGMP-Dependent+Protein+Kinases
Kinases: Serine/threonine-specific protein kinases (primarily EC 2.7.11)
Pyruvate dehydrogenase kinase - Protein kinase A - Protein kinase G - Protein kinase C (Protein kinase Mζ) - Rhodopsin - Beta adrenergic receptor - G-protein coupled receptor kinases - Ca2+/calmodulin-dependent - Myosin light-chain) - Phosphorylase - Cyclin-dependent - Mitogen-activated (Extracellular signal-regulated, C-Jun N-terminal, P38 mitogen-activated protein) - MAP3K - GSK-3 - AMP-activated
|18.104.22.168, or unknown||
Anti-Mullerian hormone receptor - Ataxia telangiectasia mutated - Aurora (A, B) - Mammalian target of rapamycin - Bone morphogenetic protein receptors (1, 2) - CDKL5 - c-Raf - EIF-2 - Ribosomal s6 - Protein kinase B - PDK1
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