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, res ...

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 Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...

. 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 cla ...

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, 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 phos ...

, 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 Fusion, or synthesis, is the process of combining two or more distinct entities into a new whole. Fusion may also refer to: Science and technology Physics *Nuclear fusion, multiple atomic nuclei combining to form one or more different atomic nucl ...

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 neopla ...

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

CDC2 Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in th ...

-mediated phosphorylation, 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 (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 Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

. 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 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

, a characteristic abnormality in chronic myelogenous leukemia (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 Philadel ...

s are also under development to inhibit BCR-ABL mutants resistant to imatinib.

Interactions

''ABL'' gene has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: * ABI1, *

ABI2 Abl interactor 2 also known as Abelson interactor 2 (Abi-2) is a protein that in humans is encoded by the ''ABI2'' gene. Interactions ABI2 has been shown to interact with ABL1, ADAM19 ADAM19 (A Disintegrin And Metalloproteinase 19, MADDAM, ...

, *

ABL2 Tyrosine-protein kinase ABL2 also known as Abelson-related gene (Arg) is an enzyme that in humans is encoded by the ''ABL2'' gene. Function ABL2 is a cytoplasmic tyrosine kinase which is closely related to but distinct from ABL1. The simila ...

, * ATM, *

BCAR1 Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the ''BCAR1'' gene. Gene BCAR1 is localized on chromosome 16 on region q, on the negative strand and it consists of seven exons. Eight different gene is ...

, * 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 pathw ...

, *

DOK1 Docking protein 1 is a protein that in humans is encoded by the ''DOK1'' gene. Function Docking protein 1 is constitutively tyrosine phosphorylated in hematopoietic progenitors isolated from chronic myelogenous leukemia (CML) patients in the c ...

, *

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 hy ...

, *

GRB10 Growth factor receptor-bound protein 10 also known as insulin receptor-binding protein Grb-IR is a protein that in humans is encoded by the ''GRB10'' gene. Function The product of this gene belongs to a small family of adaptor proteins that are ...

, *

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, * 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 Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the ''NEDD9'' gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (C ...

, *

NTRK1 Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the ''NTRK1'' gen ...

, * P73, * PAG1, *

PAK2 Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the ''PAK2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''gen ...

, *

PSTPIP1 Proline-serine-threonine phosphatase-interacting protein 1 is an enzyme that in humans is encoded by the ''PSTPIP1'' gene. Interactions PSTPIP1 has been shown to interact with: * Abl gene, * BZW1, * CD2, * PTPN12, * PTPN18, and * Wisko ...

, *

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 buddin ...

, * RAD51, * RB1, * RFX1, *

RYBP RING1 and YY1-binding protein is a protein that in humans is encoded by the ''RYBP'' gene. Interactions RYBP has been shown to interact with: * Abl gene, * CBX2, * Caspase 10, * E2F2, * E2F3, * Mdm2, * RING1, and * YY1 YY1 (Yin Yan ...

, *

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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of pro ...

, *

SORBS2 ArgBP2 protein, also referred to as Sorbin and SH3 domain-containing protein 2 is a protein that in humans is encoded by the ''SORBS2'' gene. ArgBP2 belongs to the a small family of adaptor proteins having sorbin homology (SOHO) domains. ArgBP2 is ...

, *

SPTA1 Spectrin alpha chain, erythrocyte is a protein that in humans is encoded by the ''SPTA1'' gene. Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the deter ...

, *

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 Z-disc structures, co ...

, *

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 pro ...

, *

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 YTH domain-containing protein 1 is a protein that in humans is encoded by the ''YTHDC1'' gene. YTHDC1 is a nuclear protein involved in splice site selection that localises to YT bodies; dynamic subnuclear compartments, which first appear at the be ...

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