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 functional change of the target protein ( substrate ) by changing enzyme activity , cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases , which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases , although additional types exist. Protein kinases are also found in bacteria and plants . Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involved in signal transduction .
20-397: H-89 is a protein kinase inhibitor with greatest effect on protein kinase A (PKA). H-89, derived from H-8 (N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide), was initially believed to act specifically as an inhibitor of PKA, being 30 times more potent than H-8 at inhibiting PKA and 10 times less potent at inhibiting protein kinase G . It achieves this through competitive inhibition of
40-415: A number ( dual-specificity kinases ) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues. Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins that share a conserved catalytic core. The structures of over 280 human protein kinases have been determined. There are
60-506: A number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine -rich stretch of residues in the vicinity of a lysine amino acid, which has been shown to be involved in ATP binding. In the central part of the catalytic domain, there is a conserved aspartic acid , which is important for the catalytic activity of
80-465: A number of signaling cascades, in particular those involved in cytokine signaling (but also others, including growth hormone ). One such receptor-associated tyrosine kinase is Janus kinase (JAK), many of whose effects are mediated by STAT proteins . ( See JAK-STAT pathway . ) Some kinases have dual-specificity kinase activities. For example, MEK (MAPKK), which is involved in the MAP kinase cascade,
100-454: A transmembrane spanning alpha helix , and an intracellular tyrosine kinase domain protruding into the cytoplasm . They play important roles in regulating cell division , cellular differentiation , and morphogenesis . More than 50 receptor tyrosine kinases are known in mammals. The extracellular domains serve as the ligand -binding part of the molecule, often inducing the domains to form homo- or heterodimers . The transmembrane element
120-419: Is a both a serine/threonine and tyrosine kinase. Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. A phosphate group from ATP is first added to a histidine residue within the kinase, and later transferred to an aspartate residue on a 'receiver domain' on a different protein, or sometimes on
140-417: Is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec ( imatinib ) and Iressa ( gefitinib ). Drug developments for kinase inhibitors are started from kinase assays Archived 2014-11-26 at
160-675: Is a secreted protein or a steroid hormone . Growth factors are important for regulating a variety of cellular processes. Growth factors typically act as signaling molecules between cells. Examples are cytokines and hormones that bind to specific receptors on the surface of their target cells . They often promote cell differentiation and maturation, which varies between growth factors. For example, epidermal growth factor (EGF) enhances osteogenic differentiation ( osteogenesis or bone formation), while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation ( angiogenesis ). Growth factor
180-432: Is a single α helix. The intracellular or cytoplasmic Protein kinase domain is responsible for the (highly conserved) kinase activity, as well as several regulatory functions. Ligand binding causes two reactions: Autophosphorylation stabilizes the active conformation of the kinase domain. When several amino acids suitable for phosphorylation are present in the kinase domain (e.g., the insulin-like growth factor receptor),
200-578: Is sometimes used interchangeably among scientists with the term cytokine . Historically, cytokines were associated with hematopoietic (blood and lymph forming) cells and immune system cells (e.g., lymphocytes and tissue cells from spleen , thymus , and lymph nodes ). For the circulatory system and bone marrow in which cells can occur in a liquid suspension and not bound up in solid tissue , it makes sense for them to communicate by soluble, circulating protein molecules . However, as different lines of research converged, it became clear that some of
220-515: The Wayback Machine , the lead compounds are usually profiled for specificity before moving into further tests. Many profiling services are available from fluorescent-based assays to radioisotope based detections , and competition binding assays . Growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation , wound healing , and occasionally cellular differentiation . Usually it
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#1732791833565240-574: The adenosine triphosphate (ATP) site on the PKA catalytic subunit. However, subsequent work has suggested a variety of additional effects such as inhibition of other protein kinases ( IC 50 values of 80, 120, 135, 270, 2600 and 2800 nM for S6K1 , MSK1 , PKA , ROCKII , PKBα and MAPKAP-K1b respectively), and direct inhibition of various potassium currents. In addition to its use in studying mechanisms of cell signalling, H-89 has also been used experimentally in vivo . H-89 has been shown to increase
260-476: The activity of the kinase can increase with the number of phosphorylated amino acids; in this case, the first phosphorylation switches the kinase from "off" to "standby". The active tyrosine kinase phosphorylates specific target proteins, which are often enzymes themselves. An important target is the ras protein signal-transduction chain. Tyrosine kinases recruited to a receptor following hormone binding are receptor-associated tyrosine kinases and are involved in
280-540: The enzyme. Serine/threonine protein kinases ( EC 2.7.11.1 ) phosphorylate the OH group of serine or threonine (which have similar side chains). Activity of these protein kinases can be regulated by specific events (e.g., DNA damage), as well as numerous chemical signals, including cAMP / cGMP , diacylglycerol , and Ca / calmodulin . One very important group of protein kinases are the MAP kinases (acronym from: "mitogen-activated protein kinases"). Important subgroups are
300-447: The kinase and are required to maintain the kinase in an active conformation. Tyrosine -specific protein kinases ( EC 2.7.10.1 and EC 2.7.10.2 ) phosphorylate tyrosine amino acid residues, and like serine/threonine-specific kinases are used in signal transduction . They act primarily as growth factor receptors and in downstream signaling from growth factors. Some examples include: These kinases consist of extracellular domains,
320-410: The kinase itself. The aspartyl phosphate residue is then active in signaling. Histidine kinases are found widely in prokaryotes, as well as in plants, fungi and eukaryotes. The pyruvate dehydrogenase family of kinases in animals is structurally related to histidine kinases, but instead phosphorylate serine residues, and probably do not use a phospho-histidine intermediate. Deregulated kinase activity
340-487: The kinases of the ERK subfamily, typically activated by mitogenic signals, and the stress-activated protein kinases JNK and p38. While MAP kinases are serine/threonine-specific, they are activated by combined phosphorylation on serine/threonine and tyrosine residues. Activity of MAP kinases is restricted by a number of protein phosphatases, which remove the phosphate groups that are added to specific serine or threonine residues of
360-670: The same signaling proteins which the hematopoietic and immune systems use were also being used by all sorts of other cells and tissues, during development and in the mature organism. While growth factor implies a positive effect on cell proliferation , cytokine is a neutral term with respect to whether a molecule affects proliferation. While some cytokines can be growth factors, such as G-CSF and GM-CSF , others have an inhibitory effect on cell growth or cell proliferation. Some cytokines, such as Fas ligand , are used as "death" signals; they cause target cells to undergo programmed cell death or apoptosis . The nerve growth factor (NGF)
380-407: The threshold and latency of pentylenetetrazol -induced seizures and decrease morphine withdrawal symptoms in mice. Protein kinase The chemical activity of a protein kinase involves removing a phosphate group from ATP and covalently attaching it to one of three amino acids that have a free hydroxyl group . Most kinases act on both serine and threonine , others act on tyrosine , and
400-571: Was first discovered by Rita Levi-Montalcini , which won her a Nobel Prize in Physiology or Medicine . Individual growth factor proteins tend to occur as members of larger families of structurally and evolutionarily related proteins. There are many families, some of which are listed below: The alpha granules in blood platelets contain growth factors PDGF, IGF-1, EGF, and TGF-β which begin healing of wounds by attracting and activating macrophages , fibroblasts , and endothelial cells . For
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