Tyrosine-protein kinase ABL1

Function

The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response such as DNA repair. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1.

A characteristic translocation, t(9;22), results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in many cases of chronic myelogenous leukemia.

The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2–11.

Clinical significance

This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.

The resulting BCR-ABL1 fusion protein exhibits constitutive tyrosine kinase activity and activates multiple downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and Src family kinases, which promote uncontrolled cell proliferation and survival. This can also lead to a clonal myeloproliferative disorder.

The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle. Second generation BCR-ABL tyrosine-kinase inhibitors are also under development to inhibit BCR-ABL mutants resistant to imatinib.

Interactions

ABL gene has been shown to interact with:

• ABI1,
• ABI2,
• ABL2,
• ATM,
• BCAR1,
• BCR,
• BRCA1,
• CAT,
• CBL,
• CRKL,
• DOK1,
• EPHB2,
• GPX1,
• GRB10,
• MTOR,
• GRB2,
• MDM2,
• NCK1,
• NEDD9,
• NTRK1,
• P73,
• PAG1,
• PAK2,
• PSTPIP1,
• RAD9A,
• RAD51,
• RB1,
• RFX1,
• RYBP,
• SHC1,
• SORBS2,
• SPTA1,
• SPTAN1,
• TERF1,
• VAV1, and
• YTHDC1.

Regulation

There is some evidence that the expression of Abl is regulated by the microRNA miR-203.