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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

(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 The Abelson murine leukemia virus (Ab-MLV or A-MuLV) is a retrovirus (Class VI) used to induce malignant transformation of murine lymphoid cells. As a retrovirus, it has a single-stranded, positive sense RNA genome which replicates via a DNA int ...

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 cla ...

that has been implicated in processes of cell differentiation,

cell division Cell division is the process by which a parent cell (biology), 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 eukar ...

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_junction, cell junc ...

, and stress response such as

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

. 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 ph ...

, and deletion of the SH3 domain turns ABL1 into an

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.

. The t(9;22) translocation results in the head-to-tail fusion of the '' BCR'' and ''ABL1'' genes, leading to a

fusion gene In genetics, 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 ...

present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

, 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 Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

. This, in turn, allows the cell to become

cancerous Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. 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 an abnormal version of chromosome 22 where a part of the ''ABL (gene), Abelson murine leukemia'' 1 (''ABL1'') gene on chromosome 9 breaks off and attaches to the ''BCR (gene), break ...

, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce 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 sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

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 targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases ...

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

. 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 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''), also referred to as the domestic cat or house cat, is a small domesticated carnivorous mammal. It is the only domesticated species of the family Felidae. Advances in archaeology and genetics have shown that the ...

, * 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 pat ...

, * 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 Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the ''GPX1'' gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of h ...

, * GRB10, *

MTOR The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...

, *

GRB2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...

, * 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 fro ...

, * NEDD9, * NTRK1, *

P73 p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized ...

, * PAG1, * PAK2, * PSTPIP1, *

RAD9A Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the ''RAD9A'' gene.''Rad9'' has been shown to induce G2 arrest in the cell cycle in response to DNA damage in yeast cells. ''Rad9'' was originally found in budd ...

, *

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 t ...

, * RB1, * RFX1, * 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 A ( or ) was a poet as represented in Old ...

, * SORBS2, * SPTA1, *

SPTAN1 Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the ''SPTAN1'' gene. Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at sarcomere, Z-disc str ...

, *

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 prod ...

, *

VAV1 Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene. Function The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...

, 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