UniProt functional annotation for P00520



	UniProt functional annotation for P00520

UniProt code: P00520.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: 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. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (By similarity). 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 the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. Regulates T-cell differentiation in a TBX21-dependent manner (PubMed:21690296). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (PubMed:21690296). {ECO:0000250|UniProtKB:P00519, ECO:0000269|PubMed:11279004, ECO:0000269|PubMed:11279131, ECO:0000269|PubMed:11350980, ECO:0000269|PubMed:12107171, ECO:0000269|PubMed:12748290, ECO:0000269|PubMed:14993293, ECO:0000269|PubMed:19878872, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:21690296, ECO:0000269|PubMed:7780740, ECO:0000269|PubMed:8194526, ECO:0000269|PubMed:9109492}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:10988075, ECO:0000269|PubMed:12748290, ECO:0000269|PubMed:19878872, ECO:0000269|PubMed:20072125};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:12748290}; Note=Mg(2+) and Mn(2+) were both present in the kinase buffer but Mg(2+) is likely to be the in vivo cofactor. {ECO:0000305};

Activity 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 (By similarity). Activated by RIN1 binding to the SH2 and SH3 domains. Also stimulated by cell death inducers and DNA-damage (By similarity). Phosphatidylinositol 4,5-bisphosphate (PIP2), a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits also the tyrosine kinase activity. Inhibited by imatinib mesylate (Gleevec). {ECO:0000250, ECO:0000269|PubMed:10988075, ECO:0000269|PubMed:12654251, ECO:0000269|PubMed:12748290, ECO:0000269|PubMed:14993293, ECO:0000269|PubMed:20072125, ECO:0000269|PubMed:9109492}.

Subunit: Interacts with INPPL1/SHIP2. Interacts with SORBS1 following insulin stimulation. Found in a trimolecular complex containing CDK5 and CABLES1. Interacts with CABLES1 and PSTPIP1. Interacts with ZDHHC16. 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-734 and sequesters ABL1 into the cytoplasm. Interacts (via SH3 domain) with CASP9; the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation (By similarity). Interacts with ABI1, ABI2, BCR, CRK, FYN, 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. Interacts with STX17; probably phosphorylates STX17 (By similarity). Interacts with ITGB1, HCK and FGR. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (By similarity). Interacts with TBX21 (PubMed:21690296). {ECO:0000250|UniProtKB:P00519, ECO:0000269|PubMed:10896159, ECO:0000269|PubMed:11163214, ECO:0000269|PubMed:11279004, ECO:0000269|PubMed:12021275, ECO:0000269|PubMed:12748290, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:21690296}.

Subcellular location: Cytoplasm, cytoskeleton. Nucleus. Mitochondrion. Note=The myristoylated c-ABL protein is reported to be nuclear. Sequestered into the cytoplasm through interaction with 14-3-3 proteins (By similarity). Localizes to mitochondria in response to oxidative stress. {ECO:0000250}.

Tissue specificity: Widely expressed.

Ptm: Acetylated at Lys-710 by EP300 which promotes the cytoplasmic translocation. {ECO:0000250}.

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 (By similarity). Phosphorylation at Tyr-226 and Tyr-393 correlate with increased activity (By similarity). DNA damage-induced activation of ABL1 requires the function of ATM and Ser-446 phosphorylation. Phosphorylation at Thr-547 and Ser-569 has been attributed to a CDC2-associated kinase and is coupled to cell division. Phosphorylation at Ser-618 and Ser-619 by PAK2 increases binding to CRK and reduces binding to ABI1 (By similarity). Phosphorylation on Thr-734 is required for binding 14-3-3 proteins for cytoplasmic translocation (By similarity). Phosphorylated by PDGFRB and PRKDC. {ECO:0000250, ECO:0000269|PubMed:10988075, ECO:0000269|PubMed:12748290, ECO:0000269|PubMed:14993293, ECO:0000269|PubMed:1566087, ECO:0000269|PubMed:19903482, ECO:0000269|PubMed:2183353, ECO:0000269|PubMed:9109492}.

Ptm: Polyubiquitinated. Polyubiquitination of ABL1 leads to degradation (By similarity). {ECO:0000250}.

Ptm: Isoform IV is myristoylated on Gly-2. {ECO:0000269|PubMed:12654251}.

Disruption phenotype: Mutants are born with the expected Mendelian frequency, but fail to thrive and most die within three weeks after birth. Most mutants are runted, and have atrophied thymuses with severe thymocyte deficiency. Mutants that survive to weaning age are most often runted, and about half of them show lymphopenia. They display a major reduction in the number of pre-B and immature B-cell classes in bone marrow with a wide variation between individuals, but essentially normal mature B-cell levels. Mutants are highly susceptible to infections. {ECO:0000269|PubMed:2065352, ECO:0000269|PubMed:2065353}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. ABL subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		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. In response to oxidative stress, phosphorylates serine/threonine kinase PRKD2 at 'Tyr-717' (By similarity). 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 the caspase CASP9 on 'Tyr-191' and regulates its processing in the apoptotic response to DNA damage. Phosphorylates PSMA7 that leads to an inhibition of proteasomal activity and cell cycle transition blocks. Regulates T-cell differentiation in a TBX21-dependent manner (PubMed:21690296). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (PubMed:21690296). {ECO:0000250\|UniProtKB:P00519, ECO:0000269\|PubMed:11279004, ECO:0000269\|PubMed:11279131, ECO:0000269\|PubMed:11350980, ECO:0000269\|PubMed:12107171, ECO:0000269\|PubMed:12748290, ECO:0000269\|PubMed:14993293, ECO:0000269\|PubMed:19878872, ECO:0000269\|PubMed:19903482, ECO:0000269\|PubMed:21690296, ECO:0000269\|PubMed:7780740, ECO:0000269\|PubMed:8194526, ECO:0000269\|PubMed:9109492}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:10988075, ECO:0000269\|PubMed:12748290, ECO:0000269\|PubMed:19878872, ECO:0000269\|PubMed:20072125};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:12748290}; Note=Mg(2+) and Mn(2+) were both present in the kinase buffer but Mg(2+) is likely to be the in vivo cofactor. {ECO:0000305};
Activity 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 (By similarity). Activated by RIN1 binding to the SH2 and SH3 domains. Also stimulated by cell death inducers and DNA-damage (By similarity). Phosphatidylinositol 4,5-bisphosphate (PIP2), a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits also the tyrosine kinase activity. Inhibited by imatinib mesylate (Gleevec). {ECO:0000250, ECO:0000269\|PubMed:10988075, ECO:0000269\|PubMed:12654251, ECO:0000269\|PubMed:12748290, ECO:0000269\|PubMed:14993293, ECO:0000269\|PubMed:20072125, ECO:0000269\|PubMed:9109492}.
Subunit:		Interacts with INPPL1/SHIP2. Interacts with SORBS1 following insulin stimulation. Found in a trimolecular complex containing CDK5 and CABLES1. Interacts with CABLES1 and PSTPIP1. Interacts with ZDHHC16. 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-734 and sequesters ABL1 into the cytoplasm. Interacts (via SH3 domain) with CASP9; the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation (By similarity). Interacts with ABI1, ABI2, BCR, CRK, FYN, 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. Interacts with STX17; probably phosphorylates STX17 (By similarity). Interacts with ITGB1, HCK and FGR. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (By similarity). Interacts with TBX21 (PubMed:21690296). {ECO:0000250\|UniProtKB:P00519, ECO:0000269\|PubMed:10896159, ECO:0000269\|PubMed:11163214, ECO:0000269\|PubMed:11279004, ECO:0000269\|PubMed:12021275, ECO:0000269\|PubMed:12748290, ECO:0000269\|PubMed:19903482, ECO:0000269\|PubMed:21690296}.
Subcellular location:		Cytoplasm, cytoskeleton. Nucleus. Mitochondrion. Note=The myristoylated c-ABL protein is reported to be nuclear. Sequestered into the cytoplasm through interaction with 14-3-3 proteins (By similarity). Localizes to mitochondria in response to oxidative stress. {ECO:0000250}.
Tissue specificity:		Widely expressed.
Ptm:		Acetylated at Lys-710 by EP300 which promotes the cytoplasmic translocation. {ECO:0000250}.
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 (By similarity). Phosphorylation at Tyr-226 and Tyr-393 correlate with increased activity (By similarity). DNA damage-induced activation of ABL1 requires the function of ATM and Ser-446 phosphorylation. Phosphorylation at Thr-547 and Ser-569 has been attributed to a CDC2-associated kinase and is coupled to cell division. Phosphorylation at Ser-618 and Ser-619 by PAK2 increases binding to CRK and reduces binding to ABI1 (By similarity). Phosphorylation on Thr-734 is required for binding 14-3-3 proteins for cytoplasmic translocation (By similarity). Phosphorylated by PDGFRB and PRKDC. {ECO:0000250, ECO:0000269\|PubMed:10988075, ECO:0000269\|PubMed:12748290, ECO:0000269\|PubMed:14993293, ECO:0000269\|PubMed:1566087, ECO:0000269\|PubMed:19903482, ECO:0000269\|PubMed:2183353, ECO:0000269\|PubMed:9109492}.
Ptm:		Polyubiquitinated. Polyubiquitination of ABL1 leads to degradation (By similarity). {ECO:0000250}.
Ptm:		Isoform IV is myristoylated on Gly-2. {ECO:0000269\|PubMed:12654251}.
Disruption phenotype:		Mutants are born with the expected Mendelian frequency, but fail to thrive and most die within three weeks after birth. Most mutants are runted, and have atrophied thymuses with severe thymocyte deficiency. Mutants that survive to weaning age are most often runted, and about half of them show lymphopenia. They display a major reduction in the number of pre-B and immature B-cell classes in bone marrow with a wide variation between individuals, but essentially normal mature B-cell levels. Mutants are highly susceptible to infections. {ECO:0000269\|PubMed:2065352, ECO:0000269\|PubMed:2065353}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. ABL subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.