Tyrosinkinase ABL1

The tyrosine kinase ABL1 (acronym for Abelson murine leukemia viral oncogene homolog 1, also c-Abl,p150) is a protein of the tyrosine kinase family found in various body cells. This protein enzyme 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 eponymous protooncogene c-abl, a precursor of a potentially cancer-causing gene. The exchange (translocation) of chromosome fragments between chromosome 9, which harbours c-abl, and chromosome 22, which harbours the bcr gene, resulting in the so-called Philadelphia chromosome, gives rise to a new bcr-abl gene.

This was the first oncogene found to be formed by chromosomal alterations. The bcr-abl gene is detected in 95% of chronic myeloid leukemias (CML), among others. Abl proteins are therefore popular targets for drug development.

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. Two different N-terminal protein sequences can be formed by different splicing. The N-terminus of c-Abl, which in the case of splice variant 1B additionally carries a myristylation site, is responsible for autoinhibition. A binding site for myristic acid residues could be identified in the C-lobe of the kinase function.

Activation and regulation: c-Abl exists in a basally inactive state. The N-terminal portion of the protein and the myristyl residue are thought to be responsible for the inactivity. However, other proteins modified with fatty acids, such as Fus1, may also be involved in stabilizing the inactive state. Complete absence of the terminus, such as in the case of the oncogenic viral derivative v-Abl and the oncogenic mutant BCR-Abl, is associated with constitutive activity of kinase function and cancer-initiating 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.

1. Nagar B et al.(2003) Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell. Vol. 112: 859-871.
2. Lin J et al. (2007) Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1. Oncogene 26: 6989-6996.
3. Srinivasan D et al (2006) Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells. Cancer Res 66: 5648-5655.