Linked Life Data

P00519

Source:http://identifiers.org/uniprot/P00519

Statements in which the resource exists.
SubjectPredicateObjectContext
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http://identifiers.org/unip...biopax3:commentFUNCTION: 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, ABL1 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. ABL1 targets to mitochondria in response to oxidative stress and thereby mediates mitochondrial dysfunction and cell death. ABL1 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. ABL1 acts also as a regulator of multiple pathological signaling cascades during infection. Several known tyrosine- phosphorylated microbial proteins have been identified as ABL1 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 ABL1 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, ABI1. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. COFACTOR: Magnesium or manganese. 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 (By similarity). 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. SUBUNIT: Interacts with SORBS1 following insulin stimulation. Found in a trimolecular complex containing CDK5 and CABLES1. Interacts with CABLES1 and PSTPIP1. Interacts with ZDHHC16, ITGB1 and HCK (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 ABL1 into the cytoplasm. Interacts with ABI1, ABI2, BCR, CRK, FGR, FYN, HCK, LYN, PSMA7 RAD9A, RAD51, RAD52, TP73 and WASF3. A complex made of ABL1, CTTN and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement. 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). SUBCELLULAR LOCATION: Isoform IB: Nucleus membrane; Lipid-anchor. Note=The myristoylated c-ABL protein is reported to be nuclear. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=IA; IsoId=P00519-1; Sequence=Displayed; Name=IB; IsoId=P00519-2; Sequence=VSP_004957; Note=Myristoylated on Gly-2; TISSUE SPECIFICITY: Widely expressed. PTM: Acetylated at Lys-711 by EP300 which promotes the cytoplasmic translocation. PTM: 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 ABL1 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). PTM: Polyubiquitinated. Polyubiquitination of ABL1 leads to degradation. PTM: Isoform IB is myristoylated on Gly-2. DISEASE: Note=A chromosomal aberration involving ABL1 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). SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. ABL subfamily. SIMILARITY: Contains 1 protein kinase domain. SIMILARITY: Contains 1 SH2 domain. SIMILARITY: Contains 1 SH3 domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/ABL.html"; WEB RESOURCE: Name=CGP resequencing studies; URL="http://www.sanger.ac.uk/perl/genetics/CGP/cgp_viewer?action=gene&ln=ABL1"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/abl1/"; WEB RESOURCE: Name=Wikipedia; Note=Abl entry; URL="http://en.wikipedia.org/wiki/Abl_gene"; GENE SYNONYMS:ABL1 ABL JTK7. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.lld:biopax3
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http://identifiers.org/unip...biopax3:nameAbelson murine leukemia viral oncogene homolog 1lld:biopax3
http://identifiers.org/unip...biopax3:nameAbelson tyrosine-protein kinase 1lld:biopax3
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