c-Abl

c-Abl belongs to the class of tyrosine kinases and is the prototype of a subfamily which includes two members, c-Abl and Arg (Abl-related gene). Both proteins are localized at the cell membrane, actin cytoskeleton and cytosol, and c-Abl is present in the nucleus as well. c-Abl is a non-receptor tyrosine kinase that participates in multiple signaling pathways linking the cell surface, cytoskeleton, and the nucleus. Recent in vitro studies have also linked c-Abl to amyloid-beta-induced toxicity and tau phosphorylation. c-Abl has been implicated in many cellular processes including differentiation, division, adhesion, death, and stress response. c-Abl is a latent tyrosine kinase that becomes activated in response to numerous extra- and intra-cellular stimuli. The c-Abl protein is a ubiquitously expressed nonreceptor tyrosine kinase involved in the development and function of many mammalian organ systems, including the immune system and bone. It regulates the cellular response to tamoxifen (TAM) through functional interaction with the estrogen receptor, which suggests c-Abl as a therapeutic target and a prognostic tumor marker for breast cancer. c-Abl also plays a key role in signaling chemokine-induced T-cell migration. In addition, c-Abl contains NLSs (nuclear localization signals) and DNA-binding sequences important for nuclear functions. c-Abl has become an important therapeutic target in human chronic myeloid leukaemia.

c-Abl Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>c-Abl

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>c-Abl

c-Abl Alternative Names

c-ABL, c-Abl , RP11-83J21.1, ABL, JTK7, bcr/abl, p150, v-abl [Homo sapiens]

c-Abl, Abl1, RP23-65P13.3, AI325092, Abl, E430008G22Rik, MGC117749 [Mus musculus]

Summaries for c-Abl

Entrez Gene summary for c-Abl:

The ABL1 protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of c-Abl protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t  translocation results in the head-to-tail fusion of the BCR   and c-Abl genes present in many cases of chronic myelogeneous leukemia. The DNA-binding activity of the ubiquitously expressed c-Abl tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for c-Abl. The ABL1 gene is expressed as either a 6- or 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.

OMIM - description for c-Abl:

The c-Abl protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Alterations of c-Abl by chromosomal rearrangement or viral transduction lead to malignant transformation, as in chronic myeloid leukemia.

Wikipedia summary for c-Abl:

c-abl Abelson murine leukemia viral oncogene homolog 1 also known as c-Abl is a protein that, in humans, is encoded by the c-Abl gene located on chromosome 9.

Human c-Abl Protein General Information

 

• Protein names: Proto-oncogene c-Abl , short name=c-Abl
• Sequence length: 1130 AA.
• Domain: SH2 domain SH3 domain
• Sequence similarities: Belongs to the protein kinase superfamily. Tyr protein kinase family. ABL subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.
• Post-translational modification: Acetylated at Lys-711 by EP300 which promotes the cytoplasmic translocation. Phosphorylation at Tyr-70 by members of the SRC family of kinases disrupts SH3 domain-based autoinhibitory interactions and intermolecular associations, such as that with ABI1, and also enhances kinase activity. Phosphorylation at Tyr-226 and Tyr-393 correlate with increased activity. DNA damage-induced activation of c-Abl requires the function of ATM and Ser-446 phosphorylation By similarity. Phosphorylation at Ser-569 has been attributed to a CDC2-associated kinase and is coupled to cell division By similarity. Phosphorylation at Ser-618 and Ser-619 by PAK2 increases binding to CRK and reduces binding to ABI1. Phosphorylation on Thr-735 is required for binding 14-3-3 proteins for cytoplasmic translocation. Phosphorylated by PRKDC By similarity. Polyubiquitinated. Polyubiquitination of c-Abl leads to degradation. Isoform IB is myristoylated on Gly-2.
• Cofactor: Magnesium or manganese.
• Subunit structure: Interacts with SORBS1 following insulin stimulation. Found in a trimolecular complex containing CDK5 and CABLES1. Interacts with CABLES1 and PSTPIP1. Interacts with ZDHHC16 and ITGB1 By similarity. Interacts with INPPL1/SHIP2. Interacts with the 14-3-3 proteins, YWHAB, YWHAE, YWHAG, YWHAH, SFN AND YWHAZ; the interaction with 14-3-3 proteins requires phosphorylation on Thr-735 and, sequesters c-Abl into the cytoplasm. Interacts with ABI1, ABI2, BCR, CRK, FGR, FYN, HCK, LYN, PSMA7 RAD9A, RAD51, RAD52, TP73 and WASF3.
• Subcellular location: Cytoplasm › cytoskeleton. Nucleus. Mitochondrion By similarity. Note: Shuttles between the nucleus and cytoplasm depending on environmental signals. Sequestered into the cytoplasm through interaction with 14-3-3 proteins. Localizes to mitochondria in response to oxidative stress By similarity.
• Tissue specificity: Widely expressed.
• Involvement in disease: Note=A chromosomal aberration involving c-Abl is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region, interactions of the N-terminal cap, and contributions from an N-terminal myristoyl group and phospholipids. Activated by autophosphorylation as well as by SRC-family kinase-mediated phosphorylation. Activated by RIN1 binding to the SH2 and SH3 domains. Also stimulated by cell death inducers and DNA-damage. Phosphatidylinositol 4,5-bisphosphate (PIP2), a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits also the tyrosine kinase activity . Inhibited by ABI1, whose activity is controlled by ABL1 itself through tyrosine phosphorylation. Also inhibited by imatinib mesylate (Gleevec) which is used for the treatment of chronic myeloid leukemia (CML), and by VX-680, an inhibitor that acts also on imanitib-resistant mutants.

General information above from UniProt

Function for c-Abl Protein

UniProtKB:

Non-receptor tyrosine-protein kinase that plays a role in many key processes linked to cell growth and survival such as cytoskeleton remodeling in response to extracellular stimuli, cell motility and adhesion, receptor endocytosis, autophagy, DNA damage response and apoptosis. Coordinates actin remodeling through tyrosine phosphorylation of proteins controlling cytoskeleton dynamics like WASF3 (involved in branch formation); ANXA1 (involved in membrane anchoring); DBN1, DBNL, CTTN, RAPH1 and ENAH (involved in signaling); or MAPT and PXN (microtubule-binding proteins). Phosphorylation of WASF3 is critical for the stimulation of lamellipodia formation and cell migration. Involved in the regulation of cell adhesion and motility through phosphorylation of key regulators of these processes such as BCAR1, CRK, CRKL, DOK1, EFS or NEDD9. Phosphorylates multiple receptor tyrosine kinases and more particularly promotes endocytosis of EGFR, facilitates the formation of neuromuscular synapses through MUSK, inhibits PDGFRB-mediated chemotaxis and modulates the endocytosis of activated B-cell receptor complexes. Other substrates which are involved in endocytosis regulation are the caveolin (CAV1) and RIN1. Moreover, c-Abl regulates the CBL family of ubiquitin ligases that drive receptor down-regulation and actin remodeling. Phosphorylation of CBL leads to increased EGFR stability. Involved in late-stage autophagy by regulating positively the trafficking and function of lysosomal components. c-Abl targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. c-Abl is also translocated in the nucleus where it has DNA-binding activity and is involved in DNA-damage response and apoptosis. Many substrates are known mediators of DNA repair: DDB1, DDB2, ERCC3, ERCC6, RAD9A, RAD51, RAD52 or WRN. Activates the proapoptotic pathway when the DNA damage is too severe to be repaired. Phosphorylates TP73, a primary regulator for this type of damage-induced apoptosis. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. c-Abl acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine-phosphorylated microbial proteins have been identified as c-Abl substrates. This is the case of A36R of Vaccinia virus, Tir (translocated intimin receptor) of pathogenic E.coli and possibly Citrobacter, CagA (cytotoxin-associated gene A) of H.pylori, or AnkA (ankyrin repeat-containing protein A) of A.phagocytophilum. Pathogens can highjack c-Abl kinase signaling to reorganize the host actin cytoskeleton for multiple purposes, like facilitating intracellular movement and host cell exit. Finally, functions as its own regulator through autocatalytic activity as well as through phosphorylation of its inhibitor, c-Abl.

Genatlas:

• c-Abl acts as the non receptor tyrosine kinase, involved in processes of cell differentiation, cell division, cell adhesion, and stress response
• in brain, c-Abl is involved in neuronal plasticity, neurite outgrowth, and neurogenesis
• c-Abl plays a critical role for signaling transduction from various receptors in leukocytes
• c-Abl promotes the induction of EGR1 through the MEK/ERK pathway in regulating apoptotic response to oxidative stress
• c-Abl plays a role in DNA repair as a regulator/coordinator of the DNA damage response
• c-Abl induces apoptosis in response to DNA damage
• c-Abl is required for beta(2) integrin-dependent neutrophil sustained adhesion and spreading
• c-Abl plays an essential role in the determination of cell fate that is related to its nuclear shuttling in response to DNA damage
• c-Abl modulates innate immune response through MAVS phosphorylation
• c-Abl is the major regulator of PARK2 function
• c-Abl participates in modulating PITX1 expression in the apoptotic response to DNA damage

Homology for human c-Abl

• ortholog to Abl1, Mus musculus
• ortholog to abl1, Danio rerio
• ortholog to ABL1, Pan troglodytes
• ortholog to Abl1, Rattusnorvegicus

Phenotype Information for c-Abl

• Gene/Locus: ABL1,c-Abl
• Phenotype: Leukemia, Philadelphia chromosome-positive, resistant to imatinib

Phenotype Information for c-Abl from OMIM (Online Mendelian Inheritance in Man)

Drugs for c-Abl

Target	Drug Name	Disease	Drug Status
c-Abl	Dasatinib	Chronic myelogenous leukemia	Launched
c-Abl	Dasatinib	Solid tumours, multiple myeloma	Phase II
c-Abl	Imatinib	Chronic myelogenous leukemia	Launched
c-Abl	Imatinib	Intestinal cancer & myeloid leukemia	Phase III
c-Abl	Imatinib	Glioma, lung, prostate, solid tumours	Phase II
c-Abl	Adenosine triphosphate	Dietary shortage	Approved
c-Abl	Nilotinib	Leukemia	Phase III
c-Abl	Nilotinib	ALL, CML, GIST	Phase II
c-Abl	AZD0530	Osteosarcoma; Hematological malignancies, solid tumours	Phase II
c-Abl	Bosutinib	Advanced Breast Cancer	Phase I/II

Drugs for c-Abl from TTD (Therapeutic Targets Database)