Tyrosine kinase ABL1
c-OJ | ||
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Partial structure of c-Abl with the domains SH2 (turquoise), SH3 (blue) and the kinase domain (green-red) in complex with the inhibitors PD166326 and myristylate based on the crystal structure PDB 2FO0 | ||
Mass / length primary structure | 1130 amino acids | |
Cofactor | Mg 2+ or Mn 2+> | |
Isoforms | 1A, 1B | |
Identifier | ||
Gene name (s) | ABL1; c-Abl; ABL; JTK7; E430008G22Rik | |
External IDs | ||
Enzyme classification | ||
EC, category | 2.7.10.2 , tyrosine kinase | |
Response type | Phosphorylation | |
Substrate | CRK, CRKL, DOK1 | |
Occurrence | ||
Parent taxon | Terrestrial vertebrates | |
Orthologue | ||
human | House mouse | |
Entrez | 25th | 11350 |
Ensemble | ENSG00000097007 | ENSMUSG00000026842 |
UniProt | P00519 | P00520 |
Refseq (mRNA) | NM_005157 | NM_001112703 |
Refseq (protein) | NP_005148 | NP_001106174 |
Gene locus | Chr 9: 130.71 - 130.89 Mb | Chr 2: 31.69 - 31.81 Mb |
PubMed search | 25th |
11350
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The tyrosine kinase ABL1 (acronym for Ab elson murine l eukemia viral oncogene homolog 1, also c-Abl , p150 ) is a protein from the family of tyrosine kinases that occurs in various body cells .
This protein is involved in many cellular processes, such as cell migration , cell adhesion , cell differentiation and apoptosis and is an important element for signal transduction via the T cell receptor . c-Abl is the gene product of the proto-oncogene c-abl , a precursor of a potentially cancer-causing gene. Through the exchange (translocation) of chromosome fragments between the c-abl harboring chromosome 9 and the chromosome 22 harboring the bcr gene , which can lead to the so-called Philadelphia chromosome , a new bcr-abl gene is created, which is the first one found by chromosome changes developed oncogene and can be detected in 95% of chronic myeloid leukemia (CML). Abl proteins are therefore popular target structures for drug development .
biochemistry
structure
c-Abl is a protein with a molecular mass of about 145 kDa, which is encoded by a gene on chromosome 9 gene locus q34. This system consists of a SH2 and SH3 domain , which are responsible for the regulation of c-Abl, and the enzyme function bearing kinase domain . The C-terminus carries binding domains for an interaction with the DNA and with actin . By different splicing , two different N-terminal protein sequences can be formed. The N-terminus of c-Abl, which in the case of splice variant 1B also has a myristylation site , is responsible for the autoinhibition. A binding site for myristic acid residues could be identified in the C-lobe of the kinase function.
Activation and regulation
c-Abl is in a basal inactive state. The N-terminal part of the protein and the myristyl residue are held responsible for the inactivity, although splice variant 1A does not have such a myristylation site. However, other proteins modified with fatty acids , such as Fus1 , can also be involved in stabilizing the inactive state . A complete absence of the term, as for example in the case of the oncogenic viral derivative v-Abl and the oncogenic mutant BCR-Abl, is associated with a constitutive activity of the kinase function and a cancer-causing potential.
c-Abl can be activated by receptor tyrosine kinases, such as the EGF receptor , and by non-receptor tyrosine kinases, such as c-Src .
further reading
- J. Lin, R. Arlinghaus: Activated c-Abl tyrosine kinase in malignant solid tumors. In: Oncogene . Volume 27, 2008, pp. 4385-4391.
Individual evidence
- ↑ B. Nagar et al .: Structural basis for the autoinhibition of c-Abl tyrosine kinase. In: Cell . Volume 112, 2003, pp. 859-871.
- ↑ J. Lin, among others: Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking expression FUS1: inhibition of c-Abl by the tumor suppressor gene product Fus1. In: Oncogene. Volume 26, 2007, pp. 6989-6996.
- ↑ D. Srinivasan, R. Plattner: Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. In: Cancer Res . Volume 66, 2006, pp. 5648-5655.