Tyrosine-protein kinase ABL1 also known as ABL1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that, in humans, is encoded by the ''ABL1''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

(previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene, which was initially isolated from the Abelson murine leukemia virus.

Function

The ''ABL1''

proto-oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

encodes a cytoplasmic and nuclear protein

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cl ...

that has been implicated in processes of cell differentiation,

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

, and stress response such as

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

. Activity of ABL1 protein is negatively regulated by its

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phosp ...

, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9;22) translocation results in the head-to-tail fusion of the '' BCR'' and ''ABL1'' genes, leading to a

fusion gene A fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neopl ...

present in many cases of chronic

myelogenous leukemia Myeloid leukemia is a type of leukemia affecting myeloid tissue. Types include: * Acute myeloid leukemia * Chronic myelogenous leukemia * Acute megakaryoblastic leukemia * Blastic plasmacytoid dendritic cell neoplasm See also * Hematological mali ...

. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

, suggesting a cell cycle function for ABL1. 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

Mutations in the ''ABL1'' gene are associated with

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...

(CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region)

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. This gene is a partner in a fusion gene with the ''BCR'' gene in the

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in Chromosome 22 (human), chromosome 22 of Leukemia, leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defe ...

, a characteristic abnormality in chronic

(CML) and rarely in some other

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

forms. The BCR-ABL transcript encodes a

, which activates mediators of the

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and sub ...

regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is

imatinib mesylate Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...

, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the

. Second generation

BCR-ABL tyrosine-kinase inhibitor Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philad ...

s 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 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...

, *

CAT The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members of ...

, * CBL, *

CRKL Crk-like protein is a protein that in humans is encoded by the CRKL gene. Function v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling path ...

, * DOK1, *

EPHB2 Ephrin type-B receptor 2 is a protein that in humans is encoded by the ''EPHB2'' gene. Function Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their stru ...

, * GPX1, * GRB10, * MTOR, * GRB2, * MDM2, *

NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from ...

, * NEDD9, * NTRK1, * P73, * PAG1, * PAK2, * PSTPIP1, * RAD9A, *

RAD51 DNA repair protein RAD51 homolog 1 is a protein encoded by the gene ''RAD51''. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the ...

, * RB1, *

RFX1 MHC class II regulatory factor RFX1 is a protein that, in humans, is encoded by the ''RFX1'' gene located on the short arm of chromosome 19. Structure The RFX1 gene is a member of the regulatory factor X (RFX) gene family, which encodes tra ...

, * RYBP, *

SHC1 SHC-transforming protein 1 is a protein that in humans is encoded by the ''SHC1'' gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells. SCOP classifies the 3D structure as belonging to t ...

, * SORBS2, * SPTA1, * SPTAN1, *

TERF1 Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the ''TERF1'' gene. Gene The human TERF1 gene is located in the chromosome 8 at 73,921,097-73,960,357 bp. Two transcripts of this gene are alternatively spliced produ ...

, * VAV1, and * YTHDC1.

Regulation

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

References

External links

* * (ABL) *
''Drosophila'' ''Abl tyrosine kinase'' - The Interactive Fly

ABL1
Info with links in th
Cell Migration Gateway

on the Atlas of Genetics and Oncology * * * {{Portal bar, Biology, border=no Tyrosine kinases