| Protein tyrosine kinase | ||
|---|---|---|
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| Tyrosine-protein kinase zap-70 | ||
| Identifiers | ||
| Symbol | Pkinase_Tyr | |
| Pfam | PF07714 | |
| InterPro | IPR001245 | |
| SMART | TyrKc | |
| SCOP | 1apm | |
| Available PDB structures:
1qcfA:262-511 1ad5A:262-511 2hckB:262-511 3lck :245-494 1qpdA:245-494 1qpeA:245-494 1qpcA:245-494 1qpjA:245-494 1kswA:270-519 1fmk :270-519 2src :270-519 1yojB:270-519 1y57A:270-519 1yomB:270-519 1yolA:270-519 2ptkA:267-516 1m52A:242-493 1opjA:242-493 1fpuA:242-493 1iepB:242-493 1opkA:242-493 1oplA:242-493 2f4jA:242-493 1jpaB:629-888 1mqbA:613-871 1bygA:195-440 1k9aB:195-440 1snuB:363-612 1snxB:363-612 1sm2A:363-612 1k2pA:402-651 1mp8A:422-676 1u46B:126-385 1u4dB:126-385 1u54B:126-385 2b4sD:1023-1290 1ir3A:1023-1290 1irk :1023-1290 1i44A:1023-1290 1rqqB:1023-1290 1p14A:1023-1290 2auhA:1023-1290 1gagA:1023-1290 1p4oB:999-1266 1jqhB:999-1266 1m7nA:999-1266 1k3aA:999-1266 1r0pA:1078-1337 1r1wA:1078-1337 1lufA:574-855 1lwpA:600-958 1t45A:589-924 1qzjA:589-924 1qzkA:589-924 1pkgA:589-924 1t46A:589-924 1r01A:589-924 1rjbA:610-943 1y6aA:834-1160 1y6bA:834-1160 1vr2A:834-1160 1ywnA:834-1160 1agwA:478-754 1fgiB:478-754 1fgkB:478-754 2fgiB:478-754 1gjoA:481-757 1oecA:481-757 1xpdA:724-1005 1fvrB:824-1092 1u59A:338-593 1xbbA:370-626 1xbcA:370-626 1xbaA:370-626 2b7aB:849-1123 1z9iA:712-721 1m14A:712-968 1xkkA:712-968 1m17A:712-968 1ovcA:737-976 1yvjA:822-1095 |
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A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.
Most tyrosine kinases have an associated protein tyrosine phosphatase.
Contents |
Reaction
Protein kinases are a group of enzymes that possess a catalytic subunit which transfers the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. The enzymes fall into two broad classes, characterised with respect to substrate specificity: serine/threonine specific and tyrosine specific (this domain).[1]
Structure
There are over 100 3D structures of tyrosine kinases available at the Protein Data Bank. An example is PDB 1IRK, the crystal structure of the tyrosine kinase domain of the human insulin receptor.
Families
The tyrosine kinases are divided into two main families:
- the transmembrane receptor-linked kinases
- those that are cytoplasmic proteins
Receptor
Approximately 2000 kinases are known, and more than 90 Protein Tyrosine Kinases (PTKs) have been found in the human genome. They are divided into two classes, receptor and non-receptor PTKs. At present, 58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies. They play pivotal roles in diverse cellular activities including growth, differentiation, metabolism, adhesion, motility, death.[2] RTKs are composed of an extracellular domain, which is able to bind a specific ligand, a transmembrane domain, and an intracellular catalytic domain, which is able to bind and phosphorylate selected substrates. Binding of a ligand to the extracellular region causes a series of structural rearrangements in the RTK that lead to its enzymatic activation. In particular, movement of some parts of the kinase domain gives free access to adenosine triphosphate (ATP) and the substrate to the active site. This triggers a cascade of events through phosphorylation of intracellular proteins that ultimately transmit ("transduce") the extracellular signal to the nucleus, causing changes in gene expression. Many RTKs are involved in oncogenesis, either by gene mutation, or chromosome translocation,[3] or simply by over-expression. In every case, the result is a hyper-active kinase, that confers an aberrant, ligand-independent, non-regulated growth stimulus to the cancer cells.
Cytoplasmic/non-receptor
In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 2.7.10.2).
The first non-receptor tyrosine kinase identified was the v-src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases.
A chicken sarcoma virus was found to carry mutated versions of the normal cellular Src gene.
The mutated v-src gene has lost the normal built-in inhibition of enzyme activity that is characteristic of cellular SRC (c-src) genes. SRC family members have been found to regulate many cellular processes.
For example, the T-cell antigen receptor leads to intracellular signalling by activation of Lck and Fyn, two proteins that are structurally similar to Src.
Clinical significance
Tyrosine kinases are particularly important today because of their implications in the treatment of cancer. A mutation that causes certain tyrosine kinases to be constitutively active has been associated with several cancers. Imatinib (brand names Gleevec and Glivec) is a drug able to bind the catalytic cleft of these tyrosine kinases, inhibiting its activity.[4]
Examples
Human proteins containing this domain include:
AATK; ABL1; ABL2; ALK; AXL; BLK; BMX; BTK; CSF1R; CSK; DDR1; DDR2; EGFR; EPHA1; EPHA10; EPHA2; EPHA3; EPHA4; EPHA5; EPHA6; EPHA7; EPHA8; EPHB1; EPHB2; EPHB3; EPHB4; EPHB6; ERBB2; ERBB3; ERBB4; FER; FES; FGFR1; FGFR2; FGFR3; FGFR4; FGR; FLT1; FLT3; FLT4; FRK; FYN; GSG2; HCK; IGF1R; ILK; INSR; INSRR; IRAK4; ITK; JAK1; JAK2; JAK3; KDR; KIT; KSR1; LCK; LMTK2; LMTK3; LTK; LYN; MATK; MERTK; MET; MLTK; MST1R; MUSK; NPR1; NTRK1; NTRK2; NTRK3; PDGFRA; PDGFRB; PLK4; PTK2; PTK2B; PTK6; PTK7; RET; ROR1; ROR2; ROS1; RYK; SGK493; SRC; SRMS; STYK1; SYK; TEC; TEK; TEX14; TIE1; TNK1; TNK2; TNNI3K; TXK; TYK2; TYRO3; YES1; ZAP70;
References
- ^ Hanks SK, Quinn AM, Hunter T (July 1988). "The protein kinase family: conserved features and deduced phylogeny of the catalytic domains". Science 241 (4861): 42–52. PMID 3291115.
- ^ S B Bhise, Abhijit D. Nalawade and Hitesh Wadhawa, Role of protein tyrosine kinase inhibitors in cancer therapeutics. Indian Journal of Biochemistry & Biophysics, 2004 Dec; 41: 273-280. ISSN 0301-1208.
- ^ Gunby RH, Sala E, Tartari CJ, Puttini M, Gambacorti-Passerini C, Mologni L (November 2007). "Oncogenic fusion tyrosine kinases as molecular targets for anti-cancer therapy". Anticancer Agents Med Chem 7 (6): 594–611. PMID 18045055.
- ^ Weinberg, Robert A.. The Biology Of Cancer. New York: Garland Science, Taylor & Francis Group, LLC. pp. 757–759. ISBN 0-8153-4076-1.
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