Tyrosine kinase ABL1

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c-OJ
c-OJ
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

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.

Comparison of the structural organization of c-Abl (splice variants 1a and 1b) with BCR / Abl. (BD: binding domain, NLS: nuclear localization signal , NES: nuclear export signal )

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

  1. ↑ B. Nagar et al .: Structural basis for the autoinhibition of c-Abl tyrosine kinase. In: Cell . Volume 112, 2003, pp. 859-871.
  2. ↑ 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.
  3. ↑ 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.