{"gene":"ABL1","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2003,"finding":"Crystal structures of c-Abl revealed that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto the kinase domain, forming an autoinhibited assembly structurally similar to inactive Src kinases. This explains the autoinhibitory mechanism and the differential sensitivity to imatinib (STI-571) compared to c-Src.","method":"X-ray crystallography of c-Abl protein","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional interpretation, confirmed by parallel biochemical study (PMID:12654250), two independent papers in same issue","pmids":["12654251"],"is_preprint":false},{"year":2003,"finding":"A myristoyl/phosphotyrosine switch regulates c-Abl: the intramolecular engagement of the N-terminal myristoyl modification with the kinase domain functionally replaces the SH2-domain/phosphotyrosine tail interaction in Src kinases. Phosphotyrosine ligands activate c-Abl by displacing this switch, and the mechanism explains cellular activation of c-Abl by tyrosine-phosphorylated proteins.","method":"Biochemical activity assays of purified c-Abl combined with structural analysis and mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assays plus structural data plus mutagenesis, replicated across two coordinated papers (PMID:12654251)","pmids":["12654250"],"is_preprint":false},{"year":2002,"finding":"The N-terminal 80-residue 'cap' region of c-Abl mediates autoinhibition of its catalytic activity in vitro; loss of this cap activates c-Abl and contributes to oncogenic deregulation in BCR-ABL.","method":"In vitro kinase activity assay with purified c-Abl truncation mutants; oncogenic transformation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of autoinhibition with defined domain mutants, single lab but multiple orthogonal methods","pmids":["11832214"],"is_preprint":false},{"year":1999,"finding":"c-Abl directly binds p73α via a PxxP motif in p73 engaging the SH3 domain of c-Abl, phosphorylates p73 on tyrosine residues, and this phosphorylation is required for p73-dependent apoptosis. Phosphorylation is markedly increased by gamma-irradiation.","method":"Co-immunoprecipitation, in vitro kinase assay, transient transfection with kinase-dead mutants, gamma-irradiation of cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro kinase assay, domain-mapping, and functional readout (apoptosis), widely replicated","pmids":["10391250"],"is_preprint":false},{"year":1997,"finding":"ATM binds constitutively to c-Abl via interaction of the c-Abl SH3 domain with a DPAPNPPHFP motif (residues 1373–1382) of ATM. ATM is required for radiation-induced activation of c-Abl kinase activity; c-Abl activation by ionizing radiation is diminished in ATM-deficient (ataxia telangiectasia) cells.","method":"Co-immunoprecipitation, kinase activity assays in AT cells vs. control cells, domain-mapping studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, loss-of-function in ATM-null cells, replicated across labs","pmids":["9168117"],"is_preprint":false},{"year":1997,"finding":"DNA-PK constitutively interacts with c-Abl; ionizing radiation stimulates c-Abl binding to DNA-PK and Ku antigen. DNA-PK phosphorylates and activates c-Abl in vitro. Cells deficient in DNA-PK are defective in radiation-induced c-Abl activation. In a feedback mechanism, c-Abl phosphorylates DNA-PK in vitro and inhibits DNA-PK/DNA complex formation; DNA-PK phosphorylation in vivo after irradiation is c-Abl-dependent.","method":"Co-immunoprecipitation, in vitro kinase assay, DNA-PK-deficient cell lines, irradiation experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase reconstitution, Co-IP, genetic loss-of-function cell lines, multiple orthogonal methods","pmids":["9109492"],"is_preprint":false},{"year":1994,"finding":"c-Abl binds to the first SH3 domain of c-Crk and phosphorylates c-Crk on tyrosine 221. Phosphorylation of Y221 creates an intramolecular binding site for the Crk SH2 domain, thereby inhibiting Crk protein-binding activity. This defines a mechanism by which c-Abl regulates c-Crk function.","method":"In vitro kinase assay, Co-immunoprecipitation, site-directed mutagenesis (Y221)","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus mutagenesis plus Co-IP showing functional consequence for Crk binding activity","pmids":["8194526"],"is_preprint":false},{"year":1996,"finding":"Cell adhesion to fibronectin transiently recruits c-Abl to focal contacts and triggers export of c-Abl from nucleus to cytoplasm, reactivating cytoplasmic c-Abl within 5 min. Nuclear c-Abl activity depends on adhesion and appears to originate from cytoplasmic active c-Abl that re-enters the nucleus. Cell detachment reduces kinase activity of both pools without altering distribution.","method":"Cell fractionation, kinase activity assays, immunofluorescence microscopy of focal contacts, integrin-mediated adhesion assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — fractionation with kinase assays, live-cell localization, multiple conditions with consistent results","pmids":["8986783"],"is_preprint":false},{"year":2001,"finding":"F-actin directly inhibits the kinase activity of purified c-Abl protein. The extreme C-terminal F-actin binding motif of c-Abl is required for both F-actin binding and F-actin-mediated inhibition. Deletion of this region partially restores c-Abl kinase activity in detached cells, implicating F-actin as an inhibitor contributing to reduced Abl activity upon cell detachment.","method":"In vitro kinase assay with purified c-Abl and F-actin, mutagenesis of F-actin binding domain, kinase activity in detached cells","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutagenesis plus cellular validation","pmids":["11309382"],"is_preprint":false},{"year":1996,"finding":"c-Abl kinase activity is required for ionizing radiation-induced G1 arrest. c-Abl induces p21 expression and downregulates Cdk2 activity in a p53-dependent but p21-independent manner. Cells expressing dominant-negative c-Abl or lacking c-abl are impaired in Cdk2 downregulation and G1 arrest after irradiation.","method":"Transient transfection with wild-type and kinase-inactive c-Abl, Cdk2 kinase assays, p21 expression analysis, c-abl knockout cells, p53-null and p21-null cell lines","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function (KO cells), dominant-negative approach, epistasis with p53 and p21 null cells, replicated across labs","pmids":["8717045"],"is_preprint":false},{"year":1997,"finding":"c-Abl kinase activity is required for DNA damage-induced apoptosis. Cells stably expressing kinase-inactive c-Abl or null for c-abl are resistant to ionizing radiation-induced apoptosis and clonogenic cell death. c-Abl-dependent apoptosis operates partly independent of p53.","method":"Stable expression of wild-type vs. kinase-inactive c-Abl, c-abl knockout cells, clonogenic survival assays, apoptosis measurement","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus dominant-negative plus p53-null epistasis, replicated by multiple labs","pmids":["9037071"],"is_preprint":false},{"year":2009,"finding":"c-Abl phosphorylates TAp63 on specific tyrosine residues in response to cisplatin treatment; this phosphorylation affects p63 stability and induces p63-dependent activation of proapoptotic promoters. In oocytes, this c-Abl-TAp63 pathway mediates cisplatin-induced cell death; imatinib (c-Abl inhibitor) counteracts these effects and protects the ovarian reserve.","method":"In vitro kinase assay, phospho-specific detection, imatinib treatment in cell lines and mouse oocytes, promoter activation assays","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay, phospho-specific detection, pharmacological inhibition in cells and in vivo mouse model","pmids":["19783996"],"is_preprint":false},{"year":2000,"finding":"Cytoplasmic c-Abl is activated by reactive oxygen species (H2O2). H2O2 triggers mitochondrial cytochrome c release via a c-Abl-dependent mechanism, and c-Abl-deficient cells show attenuated H2O2-induced apoptosis.","method":"Kinase activity assays in cells treated with H2O2, cytochrome c release assays, c-Abl-deficient cells","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO cells plus biochemical readout, single lab","pmids":["10770918"],"is_preprint":false},{"year":2007,"finding":"c-Abl interacts with WAVE3 upon PDGF stimulation and phosphorylates WAVE3 on four tyrosine residues. Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration; STI-571 (imatinib) blocks this phosphorylation and abrogates lamellipodia.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, imatinib inhibition, lamellipodia/migration assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase plus mutagenesis plus functional readout, single lab","pmids":["17623672"],"is_preprint":false},{"year":2004,"finding":"During cell spreading, c-Abl phosphorylates Dok1 at Y361, promoting Dok1 association with the SH2/SH3 adaptor Nck. This c-Abl–Dok1–Nck pathway is required for filopodia formation; mouse fibroblasts lacking c-Abl, Dok1, or Nck have fewer filopodia, and rescue requires each component.","method":"Unbiased substrate identification, in vitro kinase assay, site-directed mutagenesis (Y361), Co-immunoprecipitation, knockout fibroblasts, filopodia quantification","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple KO cell lines, in vitro kinase plus mutagenesis, epistasis showing mutual dependence, single lab but orthogonal methods","pmids":["15148308"],"is_preprint":false},{"year":2001,"finding":"c-Abl binds phospholipid scramblase 1 (PLSCR1) via its SH3 domain interacting with proline-rich motifs in PLSCR1, and phosphorylates PLSCR1 on Y69/Y74 in vitro. Cellular PLSCR1 tyrosine phosphorylation is reduced by STI571 or in Abl-/- cells, confirming PLSCR1 as a physiological c-Abl substrate; cisplatin increases this phosphorylation in a c-Abl-dependent manner.","method":"SH3 domain binding screen, Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, Abl-/- mouse fibroblasts, STI571 inhibition","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase plus mutagenesis plus KO cell validation, single lab","pmids":["11390389"],"is_preprint":false},{"year":2001,"finding":"Activated c-Abl is degraded by the ubiquitin-dependent 26S proteasome pathway. Activated c-Abl forms are more unstable than wild-type or kinase-inactive forms, are ubiquitinated in vivo, and their levels increase upon proteasome inhibition.","method":"Proteasome inhibitor treatment, ubiquitination assays, comparison of wild-type vs. activated vs. kinase-dead c-Abl stability","journal":"Current Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ubiquitination assay plus proteasome inhibitor rescue, single lab","pmids":["11719217"],"is_preprint":false},{"year":2002,"finding":"BRCA1 forms a constitutive complex with c-Abl via direct interaction between the PXXP motif in the BRCA1 C-terminus and the SH3 domain of c-Abl. After ionizing radiation, this complex is disrupted in an ATM-dependent manner, correlating with ATM-dependent phosphorylation of BRCA1 and enhanced c-Abl kinase activity. c-Abl phosphorylates the BRCA1 C-terminus in vitro; BRCA1-mutated cells show constitutively elevated c-Abl kinase activity.","method":"Co-immunoprecipitation, in vitro kinase assay, domain mapping (PXXP/SH3), ATM-deficient cells, irradiation experiments","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro kinase assay, domain mutants, ATM-KO epistasis, single lab","pmids":["12024016"],"is_preprint":false},{"year":1992,"finding":"c-Abl protein has sequence-specific DNA binding activity; it binds to the EP enhancer element as a nuclear complex. This DNA-binding activity is abolished in the p210 BCR-ABL mutant, consistent with its cytoplasmic localization in CML.","method":"Gel retardation/EMSA, UV cross-linking, Southwestern blot, immunological identification of c-Abl in the complex","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (EMSA, UV cross-linking, Southwestern) in one study, single lab","pmids":["1591775"],"is_preprint":false},{"year":2016,"finding":"c-Abl phosphorylates α-synuclein at tyrosine 39 (Y39), and this phosphorylation enhances α-synuclein aggregation in vitro. In hA53Tα-syn mice, c-Abl deletion reduces α-synuclein aggregation and neuropathology, while constitutively active c-Abl accelerates it. Y39-phosphorylated α-synuclein accumulates in Lewy bodies of PD patients.","method":"In vitro kinase assay, phospho-specific antibody, c-Abl knockout and overexpression in transgenic mice, α-synuclein aggregation assay, human postmortem tissue analysis","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase, mutagenesis, genetic gain- and loss-of-function in vivo, human tissue validation, single lab but multiple orthogonal methods","pmids":["27348587"],"is_preprint":false},{"year":2010,"finding":"c-Abl phosphorylates Lamellipodin (Lpd) and binds to Lpd via the Abl SH2 domain. Lpd phosphorylation by Abl positively regulates Lpd–Ena/VASP protein interaction, and efficient recruitment of Mena and EVL to the cell leading edge requires Abl kinases. Lpd cooperates with c-Abl in Ena/VASP-dependent dorsal ruffling and axonal morphogenesis.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, rescue experiments, PDGF/netrin-1 stimulation, neuronal culture","journal":"Current Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase plus siRNA KD with functional readout, single lab","pmids":["20417104"],"is_preprint":false},{"year":2008,"finding":"c-Abl is required for normal actin polymerization and lamellipodial spreading at the immune synapse in T cells, downstream TCR signaling (IL-2 production), and chemokine-induced T-cell migration. c-Abl binds phospho-HS1 via its SH2 domain, is required for full tyrosine phosphorylation of HS1, and is required for normal WAVE2 localization to the immune synapse.","method":"Kinase inhibitors, RNAi knockdown, conditional knockout mice (T-cell specific), actin polymerization assays, Co-immunoprecipitation (SH2-phospho-HS1)","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO plus RNAi plus inhibitors plus Co-IP with defined domain interaction, multiple orthogonal methods, single lab","pmids":["18305217"],"is_preprint":false},{"year":2003,"finding":"c-Abl tyrosine phosphorylation of p73α (but not p53) in response to ionizing radiation is required for p73α nuclear matrix association. This redistribution is c-Abl kinase-dependent, as STI-571 blocks p73α nuclear matrix association, and the dependency is recapitulated in the baculovirus expression system.","method":"Nuclear matrix fractionation, phospho-specific detection, STI-571 inhibition, c-Abl-defective cell lines, baculovirus co-expression","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus kinase inhibitor plus genetic-deficient cells plus heterologous system, single lab","pmids":["12824179"],"is_preprint":false},{"year":2012,"finding":"c-Abl phosphorylates MST2 at Y81 within its kinase domain. This phosphorylation disrupts MST2 interaction with Raf-1 and enhances MST2 homodimerization, thereby activating MST2 and inducing neuronal cell death. c-Abl also phosphorylates MST1 at Y433.","method":"In vitro kinase assay, immunoblotting, Co-immunoprecipitation (MST2-Raf-1 disruption), cell death assay","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase plus Co-IP disruption assay plus functional cell death readout, single lab","pmids":["22590567"],"is_preprint":false},{"year":2014,"finding":"c-Abl phosphorylates YAP at Y357, and this phosphorylation inactivates YAP oncogenic function by compromising YAP-TEAD transcriptional activity without disrupting the YAP-TEAD complex. Phosphomimetic YAP-Y357E severely compromises YAP-driven transformation, migration, anchorage-independent growth, and EMT in MCF10A cells.","method":"Reporter assays, phospho-specific antibody, site-directed mutagenesis (Y357F/E), cell transformation, migration and anchorage-independent growth assays, endogenous TEAD target gene analysis","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus multiple functional assays plus endogenous target genes, single lab","pmids":["25361080"],"is_preprint":false},{"year":2009,"finding":"c-Abl phosphorylates RAD51 on Tyr-315. This phosphorylation is required for stable RAD51 chromatin association following DNA damage but is insufficient to restore oligomerization. c-Abl associates with chromatin after DNA damage in a kinase-activity-dependent manner.","method":"Chromatin fractionation, in vitro kinase assay, RAD51 oligomerization-defective mutants, phospho-Y315 specific readout","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus in vitro kinase plus separation-of-function RAD51 mutants, single lab","pmids":["19285032"],"is_preprint":false},{"year":2010,"finding":"c-Abl and Arg (Abl-related gene) associate with and phosphorylate Galectin-3 (Gal3) via SH3 domain binding to a P80GPPSGP motif of Gal3 at Y79 and Y118. This phosphorylation impairs chaperone-mediated autophagy of Gal3, leading to its accumulation and protection of cells from apoptosis.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y79/Y118), STI571 treatment, Abl-null cells, lysosomal degradation assays","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase plus mutagenesis plus KO cells, single lab","pmids":["20150913"],"is_preprint":false},{"year":2019,"finding":"c-Abl phosphorylates PARP1 at Y829 upon LPS or TNF-α stimulation, and this tyrosine-phosphorylated PARP1 is required for poly(ADP-ribosyl)ation of RelA/p65 and NF-κB-dependent expression of proinflammatory genes. c-Abl undergoes nuclear translocation upon inflammatory stimulation.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-specific detection, c-Abl nuclear translocation assay, NF-κB reporter, siRNA knockdown, in vivo LPS model","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase plus siRNA KD plus in vivo validation, single lab","pmids":["31399520"],"is_preprint":false},{"year":2010,"finding":"c-Abl interacts with and phosphorylates MAVS (mitochondrial antiviral signaling protein) via its Card and TM domains. c-Abl activity is required for MAVS-mediated type-I IFN production and NF-κB/IRF3 activation; c-Abl knockdown impairs innate immune signaling.","method":"Co-immunoprecipitation (in vivo and in vitro), phosphotyrosine-specific antibody, c-Abl knockdown (siRNA), IFN and NF-κB reporter assays","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in vivo and in vitro plus phospho-detection plus siRNA KD with functional readout, single lab","pmids":["19914245"],"is_preprint":false},{"year":2006,"finding":"hMSH5 physically associates with c-Abl via a direct interaction between the NH2 terminus (residues 1–109) of hMSH5 and the c-Abl SH3 domain. This interaction facilitates c-Abl tyrosine kinase activation and hMSH5 phosphorylation after ionizing radiation. Tyrosine phosphorylation of hMSH5 promotes dissociation of hMSH4-hMSH5 heterocomplexes.","method":"Co-immunoprecipitation, in vitro binding assay with deletion mutants, kinase activity assay, ionizing radiation treatment","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mapping plus in vitro kinase plus functional complex disruption, single lab","pmids":["16397227"],"is_preprint":false},{"year":2002,"finding":"c-Abl phosphorylates Bruton's tyrosine kinase (Btk) at tyrosine 223 within the Btk SH3 domain. c-Abl and Btk physically interact.","method":"Co-immunoprecipitation, in vitro kinase assay with site identification","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus in vitro kinase assay, single lab, limited functional follow-up","pmids":["12445832"],"is_preprint":false},{"year":2008,"finding":"DNA mismatch repair (MMR)-dependent apoptosis after MNNG exposure requires c-Abl activation, which leads to upregulation of p73α and GADD45α. This MMR-dependent intrinsic apoptosis pathway is p53-independent but requires hMLH1/c-Abl/p73α/GADD45α retrograde signaling. Stable knockdown of c-Abl prevents MMR-dependent apoptosis.","method":"STI571 inhibition, stable shRNA knockdown of c-Abl/p73α/GADD45α, p53 loss-of-function approaches, apoptosis assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus stable KD plus epistasis with p53, single lab, multiple orthogonal approaches","pmids":["18480060"],"is_preprint":false},{"year":2010,"finding":"c-Abl phosphorylates ΔNp63α on multiple tyrosine residues. This phosphorylation increases ΔNp63α protein stability and induces its binding to YAP. c-Abl-dependent phosphorylation of ΔNp63α is required for cell viability, and the phosphorylation-deficient mutant cannot rescue p63 siRNA-induced cell death.","method":"Mass spectrometry (site identification in vitro and in vivo), co-immunoprecipitation (ΔNp63α–YAP), siRNA knockdown, rescue experiments, cisplatin treatment","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified sites, Co-IP, KD/rescue with phospho-mutant, single lab","pmids":["21364617"],"is_preprint":false},{"year":2019,"finding":"c-Abl phosphorylates YAP at Y357 downstream of integrin α5β1 activation by oscillatory shear stress (OSS), promoting YAP nuclear translocation in endothelial cells and atherogenic gene expression. Pharmacological inhibition of c-Abl attenuates OSS-induced YAPY357 phosphorylation and reduces atherosclerosis in Apoe-/- mice.","method":"Phospho-specific antibody, c-Abl inhibitor treatment, integrin α5β1 blocking peptide, Apoe-/- mouse atherosclerosis model, mechanistic cell studies","journal":"Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-specific detection plus pharmacological inhibition plus in vivo mouse model, single lab","pmids":["30629551"],"is_preprint":false},{"year":2018,"finding":"c-Abl directly interacts with GSK3β and phosphorylates it at tyrosine 216, activating GSK3β. This c-Abl–GSK3β axis impairs TFEB nuclear translocation, suppressing autophagy-lysosomal pathway function in neurons exposed to MPP+.","method":"Co-immunoprecipitation, in vitro kinase assay (Y216), siRNA knockdown of GSK3β, TFEB localization assay, c-Abl activator/inhibitor treatments","journal":"Toxicological Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase plus pharmacological and genetic manipulation plus TFEB localization, single lab","pmids":["30165626"],"is_preprint":false},{"year":2020,"finding":"Active c-Abl induces TFEB phosphorylation on tyrosine residues, retaining TFEB in the cytoplasm. Pharmacological or genetic c-Abl inhibition promotes TFEB nuclear translocation independently of mTORC1, thereby activating lysosomal biogenesis, autophagy, and exocytosis, and reducing cholesterol accumulation in Niemann-Pick type C models.","method":"TFEB nuclear translocation assay, phospho-tyrosine detection, c-Abl inhibition and genetic ablation, lysosomal biogenesis/autophagy assays, NPC cell and mouse models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus phospho-detection plus functional readout in disease model, single lab","pmids":["33163944"],"is_preprint":false},{"year":2021,"finding":"c-Abl phosphorylates PARIS at Y137, driving its association with KAP1 and epigenetic repression of MDM4, which leads to p53 activation and dopaminergic neurodegeneration. Inhibiting c-Abl or expressing Y137F-PARIS blocks MDM4 repression, prevents p53 activation, and ameliorates Parkinson's disease features in parkin knockout mice.","method":"In vitro kinase assay, phospho-specific antibody, Co-immunoprecipitation (PARIS-KAP1), gene expression analysis, nilotinib treatment, virally induced PARIS transgenic mice, parkin KO mice, human PD postmortem brain analysis","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase plus phospho-specific Co-IP plus multiple mouse models plus human tissue, single lab but highly orthogonal","pmids":["34581802"],"is_preprint":false},{"year":2009,"finding":"c-Abl is required for normal cardiac development; homozygous c-Abl mutant embryos and newborns on C57BL/6J background display dramatically enlarged hearts with abnormally increased cardiomyocyte proliferation during embryogenesis. This cardiac hyperplasia phenotype is largely rescued by cardiomyocyte-specific restoration of full-length c-Abl.","method":"c-Abl knockout mouse phenotyping, cardiomyocyte-specific c-Abl rescue via transgene, histology, cell cycle gene expression analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with cell-type-specific rescue, defined cellular phenotype (cardiomyocyte proliferation), single lab","pmids":["20080568"],"is_preprint":false},{"year":1998,"finding":"c-Abl directly interacts with meiotic chromosomes in pachytene spermatocytes and is required for normal spermatogenesis; Abl-/- mice exhibit defects at the pachytene stage of meiosis I.","method":"Immunolocalization on meiotic chromosomes, c-Abl knockout mouse analysis of testis phenotype","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus direct chromosomal localization, single lab","pmids":["9583675"],"is_preprint":false},{"year":2017,"finding":"ABL001 (asciminib) binds to the myristoyl pocket of ABL1 and induces formation of an inactive kinase conformation, allosterically inhibiting BCR-ABL1 kinase activity. It has distinct resistance mutation patterns from ATP-competitive inhibitors, with no shared resistance clones with nilotinib in barcoding studies. Combination of ABL001 with nilotinib eradicates CML xenograft tumours without recurrence.","method":"Biochemical binding assays (myristoyl pocket), cellular potency assays, genetic barcoding for resistance, mouse CML xenograft model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — structural/biochemical binding to myristoyl pocket, in vivo mouse model, genetic barcoding for resistance mechanism, multiple orthogonal methods","pmids":["28329763"],"is_preprint":false},{"year":2003,"finding":"c-Abl forms homo-oligomers and hetero-oligomers with Abl-interactor-1 (Abi-1) in a manner dependent on kinase activity and the intact N-terminal region of c-Abl. Oligomerization can activate c-Abl transforming potential.","method":"Co-immunoprecipitation in COS cells, in vitro binding assay, kinase-dead and N-terminal deletion mutants","journal":"Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP-based, limited mechanistic follow-up beyond the interaction","pmids":["12591740"],"is_preprint":false},{"year":2021,"finding":"c-Abl interacts with RIPK3, phosphorylates RIPK3 at a tyrosine site, and acts upstream of RIPK3 in Gaucher disease (GD). c-Abl activity is elevated in GD patient fibroblasts and GBA-null mice; genetic ablation or pharmacological inhibition of c-Abl reduces RIPK3 signaling and downstream MLKL activation.","method":"Co-immunoprecipitation, phospho-tyrosine detection on RIPK3, imatinib treatment, genetic c-Abl ablation in GD cell and mouse models","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phospho-detection plus genetic KO in disease model, single lab","pmids":["33549745"],"is_preprint":false},{"year":2016,"finding":"c-Abl regulates transferrin receptor (TfR1) endocytic fate: c-Abl inhibition redirects TfR1 from recycling to lysosomal degradation via chaperone Hsc70. c-Abl inhibition causes Hsc70 redistribution from cytosol to association with TfR1 at late endosomes/lysosomes.","method":"Imatinib treatment, c-Abl re-expression rescue, immunofluorescence microscopy, lysosome inhibitors, pharmacological Hsc70 inhibition","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus rescue plus imaging plus mechanistic dissection of Hsc70, single lab","pmids":["27226592"],"is_preprint":false},{"year":2014,"finding":"c-Abl is required for smooth muscle cell migration; knockdown of c-Abl by RNAi attenuates cell motility. c-Abl phosphorylates cortactin at Y421 upon cell adhesion and is required for profilin-1 (Pfn-1) localization to the leading edge. β1-integrin recruits c-Abl to the cell edge, and actin dynamics strengthen this recruitment.","method":"RNAi knockdown, time-lapse microscopy, phospho-cortactin antibody, Co-IP (cortactin-Pfn-1), cell-permeable peptide to disrupt cortactin-Pfn-1, β1-integrin blocking","journal":"American Journal of Physiology – Cell Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi KD plus phospho-specific detection plus Co-IP plus functional migration assay, single lab","pmids":["24477238"],"is_preprint":false},{"year":2018,"finding":"Phosphorylated nephrin recruits c-Abl in a SH2/SH3-dependent manner in podocytes; SH2/SH3-defective c-Abl cannot interact with phosphorylated nephrin. Co-expression of phosphorylated CD16/7-nephrin with c-Abl restores cytoskeletal organization in COS7 cells.","method":"Co-immunoprecipitation with domain mutants, cytochalasin D cytoskeletal disruption rescue assay, CD16/7-nephrin chimeric construct","journal":"Cell Death & Disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with mutants plus single functional rescue experiment, single lab","pmids":["29416010"],"is_preprint":false}],"current_model":"c-Abl is a non-receptor tyrosine kinase held in an autoinhibited state by intramolecular engagement of its N-terminal myristoyl group with the kinase domain (stabilizing SH2/SH3 docking), and is activated by displacement of this myristoyl latch, phosphotyrosine ligands, upstream kinases DNA-PK and ATM (in response to DNA damage), integrin-mediated cell adhesion, and reactive oxygen species; once active it phosphorylates a wide array of substrates—including p73, TAp63, YAP (Y357), α-synuclein (Y39), PARIS (Y137), RAD51 (Y315), Dok1 (Y361), WAVE3, Lamellipodin, PARP1 (Y829), GSK3β (Y216), TFEB, and MAVS—to regulate DNA damage-induced apoptosis and cell-cycle arrest (via p53/p21), actin cytoskeletal remodeling and cell migration, autophagy-lysosomal function, innate immune signaling, and neurodegeneration; activated c-Abl is downregulated by ubiquitin-proteasome-mediated degradation, and its kinase activity is directly inhibited by F-actin binding to its C-terminal domain."},"narrative":{"mechanistic_narrative":"ABL1 (c-Abl) is a non-receptor tyrosine kinase that integrates DNA-damage, adhesion, oxidative-stress and inflammatory signals into phosphorylation of substrates governing apoptosis, cell-cycle arrest, actin remodeling, autophagy-lysosomal function and neurodegeneration [PMID:8717045, PMID:9037071, PMID:27348587]. Its catalytic activity is autoinhibited by an intramolecular clamp: the N-terminal myristoyl group of c-Abl 1b docks into the kinase domain to stabilize SH2/SH3 packing in a Src-like inactive assembly, and the N-terminal cap region is required for this autoinhibition such that its loss deregulates the kinase as in BCR-ABL [PMID:12654251, PMID:11832214]. Activation is achieved by displacement of this myristoyl/phosphotyrosine switch through phosphotyrosine ligands, a mechanism exploited therapeutically by the allosteric myristoyl-pocket inhibitor asciminib [PMID:12654250, PMID:28329763]. In the DNA-damage response, c-Abl is activated by the upstream kinases ATM and DNA-PK, which bind it constitutively via its SH3 domain and are required for radiation-induced c-Abl activity [PMID:9168117, PMID:9109492]; once active it drives p53-dependent G1 arrest through p21 induction and Cdk2 downregulation, and p53-independent apoptosis via tyrosine phosphorylation of the p53-family members p73 and TAp63 [PMID:8717045, PMID:9037071, PMID:10391250, PMID:19783996]. A second major output is actin-cytoskeletal control downstream of integrin adhesion and growth-factor signaling, where adhesion to fibronectin recruits and reactivates c-Abl and F-actin binding to its C-terminal domain directly inhibits the kinase, while active c-Abl phosphorylates WAVE3, Dok1, Lamellipodin and cortactin to drive lamellipodia, filopodia and migration [PMID:8986783, PMID:11309382, PMID:17623672, PMID:15148308, PMID:20417104, PMID:24477238]. c-Abl also restrains the autophagy-lysosomal pathway by phosphorylating TFEB and activating GSK3β to block TFEB nuclear translocation [PMID:30165626, PMID:33163944], and it acts in innate immune and inflammatory signaling through MAVS and PARP1 [PMID:19914245, PMID:31399520]. In neurodegeneration, c-Abl phosphorylates α-synuclein at Y39 to enhance aggregation and phosphorylates PARIS at Y137 to drive p53-dependent dopaminergic neuron loss [PMID:27348587, PMID:34581802]. Active c-Abl is itself turned over by ubiquitin-proteasome-mediated degradation [PMID:11719217], and c-Abl is required for normal cardiac development and spermatogenesis [PMID:20080568, PMID:9583675].","teleology":[{"year":1992,"claim":"Established that c-Abl is a nuclear protein with intrinsic sequence-specific DNA-binding activity, distinguishing its normal localization from the cytoplasmic, transforming BCR-ABL form.","evidence":"EMSA, UV cross-linking and Southwestern blot identifying c-Abl in an EP enhancer complex","pmids":["1591775"],"confidence":"Medium","gaps":["Functional significance of direct DNA binding for transcription not resolved","No structural basis for the DNA contact defined"]},{"year":1994,"claim":"Defined the first concrete substrate mechanism, showing c-Abl uses its SH3 domain to engage and phosphorylate Crk, converting a substrate phosphorylation into an intramolecular regulatory switch.","evidence":"In vitro kinase assay, Co-IP and Y221 mutagenesis in cells","pmids":["8194526"],"confidence":"High","gaps":["Physiological pathway context of Crk regulation not established here"]},{"year":1996,"claim":"Linked c-Abl activity to cell-cycle control by showing it is required for radiation-induced G1 arrest via p53-dependent, p21-dependent Cdk2 downregulation.","evidence":"Dominant-negative and knockout cells, Cdk2 kinase assays, p53/p21-null epistasis","pmids":["8717045"],"confidence":"High","gaps":["Direct c-Abl substrate driving p21 induction not identified","Mechanism connecting kinase to p53 pathway left open"]},{"year":1996,"claim":"Connected c-Abl regulation to integrin adhesion, showing adhesion controls its nucleocytoplasmic distribution and reactivation.","evidence":"Cell fractionation, kinase assays and immunofluorescence of focal contacts under adhesion/detachment","pmids":["8986783"],"confidence":"High","gaps":["Molecular trigger coupling adhesion to kinase reactivation not defined"]},{"year":1997,"claim":"Identified ATM and DNA-PK as the upstream activators coupling c-Abl to DNA damage, with both binding c-Abl constitutively and being required for radiation-induced activation.","evidence":"Co-IP, domain mapping, in vitro kinase reconstitution, and ATM-null/DNA-PK-deficient cells","pmids":["9168117","9109492"],"confidence":"High","gaps":["Precise activating phosphosites on c-Abl not fully mapped","Quantitative contribution of each kinase in vivo unresolved"]},{"year":1997,"claim":"Established c-Abl kinase activity as required for DNA damage-induced apoptosis, partly independent of p53.","evidence":"Kinase-inactive stable lines, c-abl knockout cells and clonogenic survival assays","pmids":["9037071"],"confidence":"High","gaps":["Proapoptotic effectors downstream of c-Abl not all defined here"]},{"year":1999,"claim":"Identified p73 as a direct apoptotic effector, with SH3-mediated binding and tyrosine phosphorylation required for p73-dependent, radiation-enhanced apoptosis.","evidence":"Reciprocal Co-IP, in vitro kinase, kinase-dead mutants and gamma-irradiation","pmids":["10391250"],"confidence":"High","gaps":["Relative contribution of p73 versus other apoptotic outputs unclear"]},{"year":2001,"claim":"Showed c-Abl kinase activity is directly negatively regulated by F-actin binding through its C-terminal motif, linking cytoskeletal state to enzymatic output.","evidence":"In vitro kinase assay with purified c-Abl and F-actin plus F-actin-binding-domain mutants","pmids":["11309382"],"confidence":"High","gaps":["Structural mechanism of F-actin-mediated inhibition not resolved"]},{"year":2001,"claim":"Demonstrated that activated c-Abl is degraded by ubiquitin-proteasome turnover, establishing a feedback that limits active kinase levels.","evidence":"Proteasome inhibitor rescue and in vivo ubiquitination of active versus kinase-dead c-Abl","pmids":["11719217"],"confidence":"Medium","gaps":["Responsible E3 ligase not identified","Single lab"]},{"year":2002,"claim":"Defined the N-terminal cap as a structural autoinhibitory element whose loss deregulates the kinase and contributes to BCR-ABL oncogenesis.","evidence":"In vitro kinase assays with truncation mutants and transformation assays","pmids":["11832214"],"confidence":"High","gaps":["Atomic-level mechanism awaited later structural work"]},{"year":2003,"claim":"Provided the structural basis of autoinhibition, showing the myristoyl group docks into the kinase domain to lock SH2/SH3 in a Src-like inactive assembly, and defined the myristoyl/phosphotyrosine activating switch.","evidence":"X-ray crystallography plus purified-protein activity assays and mutagenesis (two coordinated Cell papers)","pmids":["12654251","12654250"],"confidence":"High","gaps":["Dynamics of switch displacement in cells not directly visualized"]},{"year":2004,"claim":"Extended c-Abl's cytoskeletal role to filopodia formation through a Dok1-Nck pathway with demonstrated mutual genetic dependence.","evidence":"Substrate identification, Y361 mutagenesis, Co-IP and knockout fibroblast rescue","pmids":["15148308"],"confidence":"High","gaps":["Upstream activation cue for spreading-induced c-Abl not fully defined"]},{"year":2009,"claim":"Generalized the p53-family apoptotic axis to TAp63, with therapeutic relevance to chemotherapy-induced oocyte death.","evidence":"In vitro kinase, phospho-detection, imatinib in cells and mouse oocytes, promoter assays","pmids":["19783996"],"confidence":"High","gaps":["Specific p63 phosphosites and stability mechanism partly undefined here"]},{"year":2009,"claim":"Placed c-Abl directly on chromatin in the DNA-damage response by phosphorylating RAD51 at Y315 to promote stable chromatin association.","evidence":"Chromatin fractionation, in vitro kinase and RAD51 oligomerization mutants","pmids":["19285032"],"confidence":"Medium","gaps":["Phosphorylation insufficient to restore oligomerization","Single lab"]},{"year":2014,"claim":"Identified YAP-Y357 as a c-Abl substrate that inactivates YAP oncogenic transcriptional output, revealing a tumor-suppressive arm of c-Abl signaling.","evidence":"Y357F/E mutagenesis, TEAD reporter and endogenous target genes, transformation/migration assays","pmids":["25361080"],"confidence":"Medium","gaps":["Reconciliation of tumor-suppressive YAP regulation with oncogenic BCR-ABL not addressed","Single lab"]},{"year":2016,"claim":"Established c-Abl as a driver of α-synuclein pathology, phosphorylating Y39 to enhance aggregation, with in vivo and human-tissue validation.","evidence":"In vitro kinase, phospho-antibody, c-Abl gain/loss in transgenic mice, aggregation assays, PD postmortem tissue","pmids":["27348587"],"confidence":"High","gaps":["Mechanism by which Y39 phosphorylation promotes aggregation not structurally defined"]},{"year":2018,"claim":"Identified c-Abl as a negative regulator of the autophagy-lysosomal pathway, acting through GSK3β-Y216 activation to block TFEB nuclear translocation.","evidence":"Co-IP, in vitro kinase at Y216, GSK3β knockdown and TFEB localization in MPP+ neurons","pmids":["30165626"],"confidence":"Medium","gaps":["Direct versus indirect TFEB regulation not separated here","Single lab"]},{"year":2020,"claim":"Showed c-Abl directly tyrosine-phosphorylates TFEB to retain it in the cytoplasm independently of mTORC1, positioning c-Abl inhibition as a lysosomal-activating strategy in lysosomal storage disease.","evidence":"Phospho-tyrosine detection, c-Abl inhibition/ablation and TFEB localization in NPC cell and mouse models","pmids":["33163944"],"confidence":"Medium","gaps":["TFEB phosphosites not mapped","Single lab"]},{"year":2021,"claim":"Defined a c-Abl-PARIS-KAP1-MDM4-p53 axis driving dopaminergic neurodegeneration, supported by multiple genetic models and human tissue.","evidence":"In vitro kinase, Y137 phospho-Co-IP, PARIS/parkin mouse models and PD postmortem brain","pmids":["34581802"],"confidence":"High","gaps":["Generalizability beyond parkin-deficient context not tested here"]},{"year":2017,"claim":"Validated the myristoyl pocket as a druggable allosteric site, with asciminib inducing the inactive conformation and showing non-overlapping resistance with ATP-competitive inhibitors.","evidence":"Myristoyl-pocket binding assays, cellular potency, resistance barcoding and CML xenografts","pmids":["28329763"],"confidence":"High","gaps":["Long-term combination durability in patients beyond xenograft models not addressed"]},{"year":null,"claim":"How the diverse activating inputs (DNA damage, adhesion, ROS, inflammation) are integrated to select among the many substrate-defined outputs—apoptotic, cytoskeletal, lysosomal, immune, neurodegenerative—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of input-to-output substrate selection","Relative weighting of nuclear versus cytoplasmic substrate pools unclear","E3 ligase governing active-c-Abl turnover unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,6,9,13,14,19,24,36]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,6,14,19,25,27,34]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[18]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,43]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,18,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[25,38]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,43]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,5,25]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,9,10,11]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[34,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,13,24,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,27,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,36,39]}],"complexes":[],"partners":["ATM","DNA-PK","P73","CRK","BRCA1","GSK3B","MAVS","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00519","full_name":"Tyrosine-protein kinase ABL1","aliases":["Abelson murine leukemia viral oncogene homolog 1","Abelson tyrosine-protein kinase 1","Proto-oncogene c-Abl","p150"],"length_aa":1130,"mass_kda":122.9,"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 (PubMed:22810897). 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' (PubMed:28428613). 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-153' 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. ABL1 also acts 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. Regulates T-cell differentiation in a TBX21-dependent manner (By similarity). Positively regulates chemokine-mediated T-cell migration, polarization, and homing to lymph nodes and immune-challenged tissues, potentially via activation of NEDD9/HEF1 and RAP1 (By similarity). Phosphorylates TBX21 on tyrosine residues leading to an enhancement of its transcriptional activator activity (By similarity)","subcellular_location":"Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/P00519/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABL1","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCKAP1","stoichiometry":0.2},{"gene":"WASF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ABL1","total_profiled":1310},"omim":[{"mim_id":"618772","title":"CDK5 AND ABL ENZYME SUBSTRATE 2; CABLES2","url":"https://www.omim.org/entry/618772"},{"mim_id":"617602","title":"CONGENITAL HEART DEFECTS AND SKELETAL MALFORMATIONS SYNDROME; CHDSKM","url":"https://www.omim.org/entry/617602"},{"mim_id":"617368","title":"SH3 DOMAIN-BINDING PROTEIN 1; SH3BP1","url":"https://www.omim.org/entry/617368"},{"mim_id":"616750","title":"ZDHHC PALMITOYLTRANSFERASE 16; ZDHHC16","url":"https://www.omim.org/entry/616750"},{"mim_id":"616458","title":"PR DOMAIN-CONTAINING PROTEIN 12; PRDM12","url":"https://www.omim.org/entry/616458"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABL1"},"hgnc":{"alias_symbol":["JTK7","c-ABL","p150"],"prev_symbol":["ABL"]},"alphafold":{"accession":"P00519","domains":[{"cath_id":"3.30.505.10","chopping":"64-215","consensus_level":"medium","plddt":94.0965,"start":64,"end":215},{"cath_id":"3.30.200.20","chopping":"236-317","consensus_level":"medium","plddt":88.1324,"start":236,"end":317},{"cath_id":"1.10.510.10","chopping":"321-510","consensus_level":"medium","plddt":93.9355,"start":321,"end":510},{"cath_id":"1.20.120","chopping":"1028-1098_1110-1128","consensus_level":"high","plddt":65.463,"start":1028,"end":1128}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00519","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00519-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00519-F1-predicted_aligned_error_v6.png","plddt_mean":63.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABL1","jax_strain_url":"https://www.jax.org/strain/search?query=ABL1"},"sequence":{"accession":"P00519","fasta_url":"https://rest.uniprot.org/uniprotkb/P00519.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00519/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00519"}},"corpus_meta":[{"pmid":"12654251","id":"PMC_12654251","title":"Structural basis for the autoinhibition of c-Abl tyrosine kinase.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12654251","citation_count":704,"is_preprint":false},{"pmid":"18827185","id":"PMC_18827185","title":"Molecular biology of bcr-abl1-positive chronic myeloid leukemia.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18827185","citation_count":547,"is_preprint":false},{"pmid":"10391250","id":"PMC_10391250","title":"Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10391250","citation_count":496,"is_preprint":false},{"pmid":"28329763","id":"PMC_28329763","title":"The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28329763","citation_count":469,"is_preprint":false},{"pmid":"9168117","id":"PMC_9168117","title":"Interaction between ATM protein and c-Abl in response to DNA damage.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9168117","citation_count":410,"is_preprint":false},{"pmid":"14708008","id":"PMC_14708008","title":"Regulation of the c-Abl and Bcr-Abl tyrosine kinases.","date":"2004","source":"Nature reviews. 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This explains the autoinhibitory mechanism and the differential sensitivity to imatinib (STI-571) compared to c-Src.\",\n      \"method\": \"X-ray crystallography of c-Abl protein\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional interpretation, confirmed by parallel biochemical study (PMID:12654250), two independent papers in same issue\",\n      \"pmids\": [\"12654251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A myristoyl/phosphotyrosine switch regulates c-Abl: the intramolecular engagement of the N-terminal myristoyl modification with the kinase domain functionally replaces the SH2-domain/phosphotyrosine tail interaction in Src kinases. Phosphotyrosine ligands activate c-Abl by displacing this switch, and the mechanism explains cellular activation of c-Abl by tyrosine-phosphorylated proteins.\",\n      \"method\": \"Biochemical activity assays of purified c-Abl combined with structural analysis and mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assays plus structural data plus mutagenesis, replicated across two coordinated papers (PMID:12654251)\",\n      \"pmids\": [\"12654250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The N-terminal 80-residue 'cap' region of c-Abl mediates autoinhibition of its catalytic activity in vitro; loss of this cap activates c-Abl and contributes to oncogenic deregulation in BCR-ABL.\",\n      \"method\": \"In vitro kinase activity assay with purified c-Abl truncation mutants; oncogenic transformation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of autoinhibition with defined domain mutants, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"11832214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"c-Abl directly binds p73α via a PxxP motif in p73 engaging the SH3 domain of c-Abl, phosphorylates p73 on tyrosine residues, and this phosphorylation is required for p73-dependent apoptosis. Phosphorylation is markedly increased by gamma-irradiation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, transient transfection with kinase-dead mutants, gamma-irradiation of cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro kinase assay, domain-mapping, and functional readout (apoptosis), widely replicated\",\n      \"pmids\": [\"10391250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ATM binds constitutively to c-Abl via interaction of the c-Abl SH3 domain with a DPAPNPPHFP motif (residues 1373–1382) of ATM. ATM is required for radiation-induced activation of c-Abl kinase activity; c-Abl activation by ionizing radiation is diminished in ATM-deficient (ataxia telangiectasia) cells.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays in AT cells vs. control cells, domain-mapping studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, loss-of-function in ATM-null cells, replicated across labs\",\n      \"pmids\": [\"9168117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"DNA-PK constitutively interacts with c-Abl; ionizing radiation stimulates c-Abl binding to DNA-PK and Ku antigen. DNA-PK phosphorylates and activates c-Abl in vitro. Cells deficient in DNA-PK are defective in radiation-induced c-Abl activation. In a feedback mechanism, c-Abl phosphorylates DNA-PK in vitro and inhibits DNA-PK/DNA complex formation; DNA-PK phosphorylation in vivo after irradiation is c-Abl-dependent.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, DNA-PK-deficient cell lines, irradiation experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase reconstitution, Co-IP, genetic loss-of-function cell lines, multiple orthogonal methods\",\n      \"pmids\": [\"9109492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Abl binds to the first SH3 domain of c-Crk and phosphorylates c-Crk on tyrosine 221. Phosphorylation of Y221 creates an intramolecular binding site for the Crk SH2 domain, thereby inhibiting Crk protein-binding activity. This defines a mechanism by which c-Abl regulates c-Crk function.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, site-directed mutagenesis (Y221)\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus mutagenesis plus Co-IP showing functional consequence for Crk binding activity\",\n      \"pmids\": [\"8194526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Cell adhesion to fibronectin transiently recruits c-Abl to focal contacts and triggers export of c-Abl from nucleus to cytoplasm, reactivating cytoplasmic c-Abl within 5 min. Nuclear c-Abl activity depends on adhesion and appears to originate from cytoplasmic active c-Abl that re-enters the nucleus. Cell detachment reduces kinase activity of both pools without altering distribution.\",\n      \"method\": \"Cell fractionation, kinase activity assays, immunofluorescence microscopy of focal contacts, integrin-mediated adhesion assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with kinase assays, live-cell localization, multiple conditions with consistent results\",\n      \"pmids\": [\"8986783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"F-actin directly inhibits the kinase activity of purified c-Abl protein. The extreme C-terminal F-actin binding motif of c-Abl is required for both F-actin binding and F-actin-mediated inhibition. Deletion of this region partially restores c-Abl kinase activity in detached cells, implicating F-actin as an inhibitor contributing to reduced Abl activity upon cell detachment.\",\n      \"method\": \"In vitro kinase assay with purified c-Abl and F-actin, mutagenesis of F-actin binding domain, kinase activity in detached cells\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins plus mutagenesis plus cellular validation\",\n      \"pmids\": [\"11309382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"c-Abl kinase activity is required for ionizing radiation-induced G1 arrest. c-Abl induces p21 expression and downregulates Cdk2 activity in a p53-dependent but p21-independent manner. Cells expressing dominant-negative c-Abl or lacking c-abl are impaired in Cdk2 downregulation and G1 arrest after irradiation.\",\n      \"method\": \"Transient transfection with wild-type and kinase-inactive c-Abl, Cdk2 kinase assays, p21 expression analysis, c-abl knockout cells, p53-null and p21-null cell lines\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function (KO cells), dominant-negative approach, epistasis with p53 and p21 null cells, replicated across labs\",\n      \"pmids\": [\"8717045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"c-Abl kinase activity is required for DNA damage-induced apoptosis. Cells stably expressing kinase-inactive c-Abl or null for c-abl are resistant to ionizing radiation-induced apoptosis and clonogenic cell death. c-Abl-dependent apoptosis operates partly independent of p53.\",\n      \"method\": \"Stable expression of wild-type vs. kinase-inactive c-Abl, c-abl knockout cells, clonogenic survival assays, apoptosis measurement\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus dominant-negative plus p53-null epistasis, replicated by multiple labs\",\n      \"pmids\": [\"9037071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Abl phosphorylates TAp63 on specific tyrosine residues in response to cisplatin treatment; this phosphorylation affects p63 stability and induces p63-dependent activation of proapoptotic promoters. In oocytes, this c-Abl-TAp63 pathway mediates cisplatin-induced cell death; imatinib (c-Abl inhibitor) counteracts these effects and protects the ovarian reserve.\",\n      \"method\": \"In vitro kinase assay, phospho-specific detection, imatinib treatment in cell lines and mouse oocytes, promoter activation assays\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay, phospho-specific detection, pharmacological inhibition in cells and in vivo mouse model\",\n      \"pmids\": [\"19783996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cytoplasmic c-Abl is activated by reactive oxygen species (H2O2). H2O2 triggers mitochondrial cytochrome c release via a c-Abl-dependent mechanism, and c-Abl-deficient cells show attenuated H2O2-induced apoptosis.\",\n      \"method\": \"Kinase activity assays in cells treated with H2O2, cytochrome c release assays, c-Abl-deficient cells\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO cells plus biochemical readout, single lab\",\n      \"pmids\": [\"10770918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"c-Abl interacts with WAVE3 upon PDGF stimulation and phosphorylates WAVE3 on four tyrosine residues. Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration; STI-571 (imatinib) blocks this phosphorylation and abrogates lamellipodia.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, imatinib inhibition, lamellipodia/migration assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase plus mutagenesis plus functional readout, single lab\",\n      \"pmids\": [\"17623672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"During cell spreading, c-Abl phosphorylates Dok1 at Y361, promoting Dok1 association with the SH2/SH3 adaptor Nck. This c-Abl–Dok1–Nck pathway is required for filopodia formation; mouse fibroblasts lacking c-Abl, Dok1, or Nck have fewer filopodia, and rescue requires each component.\",\n      \"method\": \"Unbiased substrate identification, in vitro kinase assay, site-directed mutagenesis (Y361), Co-immunoprecipitation, knockout fibroblasts, filopodia quantification\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KO cell lines, in vitro kinase plus mutagenesis, epistasis showing mutual dependence, single lab but orthogonal methods\",\n      \"pmids\": [\"15148308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"c-Abl binds phospholipid scramblase 1 (PLSCR1) via its SH3 domain interacting with proline-rich motifs in PLSCR1, and phosphorylates PLSCR1 on Y69/Y74 in vitro. Cellular PLSCR1 tyrosine phosphorylation is reduced by STI571 or in Abl-/- cells, confirming PLSCR1 as a physiological c-Abl substrate; cisplatin increases this phosphorylation in a c-Abl-dependent manner.\",\n      \"method\": \"SH3 domain binding screen, Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, Abl-/- mouse fibroblasts, STI571 inhibition\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase plus mutagenesis plus KO cell validation, single lab\",\n      \"pmids\": [\"11390389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Activated c-Abl is degraded by the ubiquitin-dependent 26S proteasome pathway. Activated c-Abl forms are more unstable than wild-type or kinase-inactive forms, are ubiquitinated in vivo, and their levels increase upon proteasome inhibition.\",\n      \"method\": \"Proteasome inhibitor treatment, ubiquitination assays, comparison of wild-type vs. activated vs. kinase-dead c-Abl stability\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ubiquitination assay plus proteasome inhibitor rescue, single lab\",\n      \"pmids\": [\"11719217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"BRCA1 forms a constitutive complex with c-Abl via direct interaction between the PXXP motif in the BRCA1 C-terminus and the SH3 domain of c-Abl. After ionizing radiation, this complex is disrupted in an ATM-dependent manner, correlating with ATM-dependent phosphorylation of BRCA1 and enhanced c-Abl kinase activity. c-Abl phosphorylates the BRCA1 C-terminus in vitro; BRCA1-mutated cells show constitutively elevated c-Abl kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, domain mapping (PXXP/SH3), ATM-deficient cells, irradiation experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro kinase assay, domain mutants, ATM-KO epistasis, single lab\",\n      \"pmids\": [\"12024016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"c-Abl protein has sequence-specific DNA binding activity; it binds to the EP enhancer element as a nuclear complex. This DNA-binding activity is abolished in the p210 BCR-ABL mutant, consistent with its cytoplasmic localization in CML.\",\n      \"method\": \"Gel retardation/EMSA, UV cross-linking, Southwestern blot, immunological identification of c-Abl in the complex\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (EMSA, UV cross-linking, Southwestern) in one study, single lab\",\n      \"pmids\": [\"1591775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"c-Abl phosphorylates α-synuclein at tyrosine 39 (Y39), and this phosphorylation enhances α-synuclein aggregation in vitro. In hA53Tα-syn mice, c-Abl deletion reduces α-synuclein aggregation and neuropathology, while constitutively active c-Abl accelerates it. Y39-phosphorylated α-synuclein accumulates in Lewy bodies of PD patients.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, c-Abl knockout and overexpression in transgenic mice, α-synuclein aggregation assay, human postmortem tissue analysis\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase, mutagenesis, genetic gain- and loss-of-function in vivo, human tissue validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27348587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Abl phosphorylates Lamellipodin (Lpd) and binds to Lpd via the Abl SH2 domain. Lpd phosphorylation by Abl positively regulates Lpd–Ena/VASP protein interaction, and efficient recruitment of Mena and EVL to the cell leading edge requires Abl kinases. Lpd cooperates with c-Abl in Ena/VASP-dependent dorsal ruffling and axonal morphogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, rescue experiments, PDGF/netrin-1 stimulation, neuronal culture\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase plus siRNA KD with functional readout, single lab\",\n      \"pmids\": [\"20417104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"c-Abl is required for normal actin polymerization and lamellipodial spreading at the immune synapse in T cells, downstream TCR signaling (IL-2 production), and chemokine-induced T-cell migration. c-Abl binds phospho-HS1 via its SH2 domain, is required for full tyrosine phosphorylation of HS1, and is required for normal WAVE2 localization to the immune synapse.\",\n      \"method\": \"Kinase inhibitors, RNAi knockdown, conditional knockout mice (T-cell specific), actin polymerization assays, Co-immunoprecipitation (SH2-phospho-HS1)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus RNAi plus inhibitors plus Co-IP with defined domain interaction, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18305217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Abl tyrosine phosphorylation of p73α (but not p53) in response to ionizing radiation is required for p73α nuclear matrix association. This redistribution is c-Abl kinase-dependent, as STI-571 blocks p73α nuclear matrix association, and the dependency is recapitulated in the baculovirus expression system.\",\n      \"method\": \"Nuclear matrix fractionation, phospho-specific detection, STI-571 inhibition, c-Abl-defective cell lines, baculovirus co-expression\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus kinase inhibitor plus genetic-deficient cells plus heterologous system, single lab\",\n      \"pmids\": [\"12824179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"c-Abl phosphorylates MST2 at Y81 within its kinase domain. This phosphorylation disrupts MST2 interaction with Raf-1 and enhances MST2 homodimerization, thereby activating MST2 and inducing neuronal cell death. c-Abl also phosphorylates MST1 at Y433.\",\n      \"method\": \"In vitro kinase assay, immunoblotting, Co-immunoprecipitation (MST2-Raf-1 disruption), cell death assay\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase plus Co-IP disruption assay plus functional cell death readout, single lab\",\n      \"pmids\": [\"22590567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Abl phosphorylates YAP at Y357, and this phosphorylation inactivates YAP oncogenic function by compromising YAP-TEAD transcriptional activity without disrupting the YAP-TEAD complex. Phosphomimetic YAP-Y357E severely compromises YAP-driven transformation, migration, anchorage-independent growth, and EMT in MCF10A cells.\",\n      \"method\": \"Reporter assays, phospho-specific antibody, site-directed mutagenesis (Y357F/E), cell transformation, migration and anchorage-independent growth assays, endogenous TEAD target gene analysis\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus multiple functional assays plus endogenous target genes, single lab\",\n      \"pmids\": [\"25361080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Abl phosphorylates RAD51 on Tyr-315. This phosphorylation is required for stable RAD51 chromatin association following DNA damage but is insufficient to restore oligomerization. c-Abl associates with chromatin after DNA damage in a kinase-activity-dependent manner.\",\n      \"method\": \"Chromatin fractionation, in vitro kinase assay, RAD51 oligomerization-defective mutants, phospho-Y315 specific readout\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus in vitro kinase plus separation-of-function RAD51 mutants, single lab\",\n      \"pmids\": [\"19285032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Abl and Arg (Abl-related gene) associate with and phosphorylate Galectin-3 (Gal3) via SH3 domain binding to a P80GPPSGP motif of Gal3 at Y79 and Y118. This phosphorylation impairs chaperone-mediated autophagy of Gal3, leading to its accumulation and protection of cells from apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y79/Y118), STI571 treatment, Abl-null cells, lysosomal degradation assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase plus mutagenesis plus KO cells, single lab\",\n      \"pmids\": [\"20150913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Abl phosphorylates PARP1 at Y829 upon LPS or TNF-α stimulation, and this tyrosine-phosphorylated PARP1 is required for poly(ADP-ribosyl)ation of RelA/p65 and NF-κB-dependent expression of proinflammatory genes. c-Abl undergoes nuclear translocation upon inflammatory stimulation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-specific detection, c-Abl nuclear translocation assay, NF-κB reporter, siRNA knockdown, in vivo LPS model\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase plus siRNA KD plus in vivo validation, single lab\",\n      \"pmids\": [\"31399520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Abl interacts with and phosphorylates MAVS (mitochondrial antiviral signaling protein) via its Card and TM domains. c-Abl activity is required for MAVS-mediated type-I IFN production and NF-κB/IRF3 activation; c-Abl knockdown impairs innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), phosphotyrosine-specific antibody, c-Abl knockdown (siRNA), IFN and NF-κB reporter assays\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in vivo and in vitro plus phospho-detection plus siRNA KD with functional readout, single lab\",\n      \"pmids\": [\"19914245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"hMSH5 physically associates with c-Abl via a direct interaction between the NH2 terminus (residues 1–109) of hMSH5 and the c-Abl SH3 domain. This interaction facilitates c-Abl tyrosine kinase activation and hMSH5 phosphorylation after ionizing radiation. Tyrosine phosphorylation of hMSH5 promotes dissociation of hMSH4-hMSH5 heterocomplexes.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay with deletion mutants, kinase activity assay, ionizing radiation treatment\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mapping plus in vitro kinase plus functional complex disruption, single lab\",\n      \"pmids\": [\"16397227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Abl phosphorylates Bruton's tyrosine kinase (Btk) at tyrosine 223 within the Btk SH3 domain. c-Abl and Btk physically interact.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with site identification\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus in vitro kinase assay, single lab, limited functional follow-up\",\n      \"pmids\": [\"12445832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA mismatch repair (MMR)-dependent apoptosis after MNNG exposure requires c-Abl activation, which leads to upregulation of p73α and GADD45α. This MMR-dependent intrinsic apoptosis pathway is p53-independent but requires hMLH1/c-Abl/p73α/GADD45α retrograde signaling. Stable knockdown of c-Abl prevents MMR-dependent apoptosis.\",\n      \"method\": \"STI571 inhibition, stable shRNA knockdown of c-Abl/p73α/GADD45α, p53 loss-of-function approaches, apoptosis assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus stable KD plus epistasis with p53, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"18480060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Abl phosphorylates ΔNp63α on multiple tyrosine residues. This phosphorylation increases ΔNp63α protein stability and induces its binding to YAP. c-Abl-dependent phosphorylation of ΔNp63α is required for cell viability, and the phosphorylation-deficient mutant cannot rescue p63 siRNA-induced cell death.\",\n      \"method\": \"Mass spectrometry (site identification in vitro and in vivo), co-immunoprecipitation (ΔNp63α–YAP), siRNA knockdown, rescue experiments, cisplatin treatment\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified sites, Co-IP, KD/rescue with phospho-mutant, single lab\",\n      \"pmids\": [\"21364617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-Abl phosphorylates YAP at Y357 downstream of integrin α5β1 activation by oscillatory shear stress (OSS), promoting YAP nuclear translocation in endothelial cells and atherogenic gene expression. Pharmacological inhibition of c-Abl attenuates OSS-induced YAPY357 phosphorylation and reduces atherosclerosis in Apoe-/- mice.\",\n      \"method\": \"Phospho-specific antibody, c-Abl inhibitor treatment, integrin α5β1 blocking peptide, Apoe-/- mouse atherosclerosis model, mechanistic cell studies\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-specific detection plus pharmacological inhibition plus in vivo mouse model, single lab\",\n      \"pmids\": [\"30629551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Abl directly interacts with GSK3β and phosphorylates it at tyrosine 216, activating GSK3β. This c-Abl–GSK3β axis impairs TFEB nuclear translocation, suppressing autophagy-lysosomal pathway function in neurons exposed to MPP+.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay (Y216), siRNA knockdown of GSK3β, TFEB localization assay, c-Abl activator/inhibitor treatments\",\n      \"journal\": \"Toxicological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase plus pharmacological and genetic manipulation plus TFEB localization, single lab\",\n      \"pmids\": [\"30165626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Active c-Abl induces TFEB phosphorylation on tyrosine residues, retaining TFEB in the cytoplasm. Pharmacological or genetic c-Abl inhibition promotes TFEB nuclear translocation independently of mTORC1, thereby activating lysosomal biogenesis, autophagy, and exocytosis, and reducing cholesterol accumulation in Niemann-Pick type C models.\",\n      \"method\": \"TFEB nuclear translocation assay, phospho-tyrosine detection, c-Abl inhibition and genetic ablation, lysosomal biogenesis/autophagy assays, NPC cell and mouse models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological inhibition plus phospho-detection plus functional readout in disease model, single lab\",\n      \"pmids\": [\"33163944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Abl phosphorylates PARIS at Y137, driving its association with KAP1 and epigenetic repression of MDM4, which leads to p53 activation and dopaminergic neurodegeneration. Inhibiting c-Abl or expressing Y137F-PARIS blocks MDM4 repression, prevents p53 activation, and ameliorates Parkinson's disease features in parkin knockout mice.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, Co-immunoprecipitation (PARIS-KAP1), gene expression analysis, nilotinib treatment, virally induced PARIS transgenic mice, parkin KO mice, human PD postmortem brain analysis\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase plus phospho-specific Co-IP plus multiple mouse models plus human tissue, single lab but highly orthogonal\",\n      \"pmids\": [\"34581802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"c-Abl is required for normal cardiac development; homozygous c-Abl mutant embryos and newborns on C57BL/6J background display dramatically enlarged hearts with abnormally increased cardiomyocyte proliferation during embryogenesis. This cardiac hyperplasia phenotype is largely rescued by cardiomyocyte-specific restoration of full-length c-Abl.\",\n      \"method\": \"c-Abl knockout mouse phenotyping, cardiomyocyte-specific c-Abl rescue via transgene, histology, cell cycle gene expression analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cell-type-specific rescue, defined cellular phenotype (cardiomyocyte proliferation), single lab\",\n      \"pmids\": [\"20080568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Abl directly interacts with meiotic chromosomes in pachytene spermatocytes and is required for normal spermatogenesis; Abl-/- mice exhibit defects at the pachytene stage of meiosis I.\",\n      \"method\": \"Immunolocalization on meiotic chromosomes, c-Abl knockout mouse analysis of testis phenotype\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus direct chromosomal localization, single lab\",\n      \"pmids\": [\"9583675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ABL001 (asciminib) binds to the myristoyl pocket of ABL1 and induces formation of an inactive kinase conformation, allosterically inhibiting BCR-ABL1 kinase activity. It has distinct resistance mutation patterns from ATP-competitive inhibitors, with no shared resistance clones with nilotinib in barcoding studies. Combination of ABL001 with nilotinib eradicates CML xenograft tumours without recurrence.\",\n      \"method\": \"Biochemical binding assays (myristoyl pocket), cellular potency assays, genetic barcoding for resistance, mouse CML xenograft model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — structural/biochemical binding to myristoyl pocket, in vivo mouse model, genetic barcoding for resistance mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"28329763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Abl forms homo-oligomers and hetero-oligomers with Abl-interactor-1 (Abi-1) in a manner dependent on kinase activity and the intact N-terminal region of c-Abl. Oligomerization can activate c-Abl transforming potential.\",\n      \"method\": \"Co-immunoprecipitation in COS cells, in vitro binding assay, kinase-dead and N-terminal deletion mutants\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP-based, limited mechanistic follow-up beyond the interaction\",\n      \"pmids\": [\"12591740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Abl interacts with RIPK3, phosphorylates RIPK3 at a tyrosine site, and acts upstream of RIPK3 in Gaucher disease (GD). c-Abl activity is elevated in GD patient fibroblasts and GBA-null mice; genetic ablation or pharmacological inhibition of c-Abl reduces RIPK3 signaling and downstream MLKL activation.\",\n      \"method\": \"Co-immunoprecipitation, phospho-tyrosine detection on RIPK3, imatinib treatment, genetic c-Abl ablation in GD cell and mouse models\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phospho-detection plus genetic KO in disease model, single lab\",\n      \"pmids\": [\"33549745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"c-Abl regulates transferrin receptor (TfR1) endocytic fate: c-Abl inhibition redirects TfR1 from recycling to lysosomal degradation via chaperone Hsc70. c-Abl inhibition causes Hsc70 redistribution from cytosol to association with TfR1 at late endosomes/lysosomes.\",\n      \"method\": \"Imatinib treatment, c-Abl re-expression rescue, immunofluorescence microscopy, lysosome inhibitors, pharmacological Hsc70 inhibition\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus rescue plus imaging plus mechanistic dissection of Hsc70, single lab\",\n      \"pmids\": [\"27226592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Abl is required for smooth muscle cell migration; knockdown of c-Abl by RNAi attenuates cell motility. c-Abl phosphorylates cortactin at Y421 upon cell adhesion and is required for profilin-1 (Pfn-1) localization to the leading edge. β1-integrin recruits c-Abl to the cell edge, and actin dynamics strengthen this recruitment.\",\n      \"method\": \"RNAi knockdown, time-lapse microscopy, phospho-cortactin antibody, Co-IP (cortactin-Pfn-1), cell-permeable peptide to disrupt cortactin-Pfn-1, β1-integrin blocking\",\n      \"journal\": \"American Journal of Physiology – Cell Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi KD plus phospho-specific detection plus Co-IP plus functional migration assay, single lab\",\n      \"pmids\": [\"24477238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Phosphorylated nephrin recruits c-Abl in a SH2/SH3-dependent manner in podocytes; SH2/SH3-defective c-Abl cannot interact with phosphorylated nephrin. Co-expression of phosphorylated CD16/7-nephrin with c-Abl restores cytoskeletal organization in COS7 cells.\",\n      \"method\": \"Co-immunoprecipitation with domain mutants, cytochalasin D cytoskeletal disruption rescue assay, CD16/7-nephrin chimeric construct\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with mutants plus single functional rescue experiment, single lab\",\n      \"pmids\": [\"29416010\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-Abl is a non-receptor tyrosine kinase held in an autoinhibited state by intramolecular engagement of its N-terminal myristoyl group with the kinase domain (stabilizing SH2/SH3 docking), and is activated by displacement of this myristoyl latch, phosphotyrosine ligands, upstream kinases DNA-PK and ATM (in response to DNA damage), integrin-mediated cell adhesion, and reactive oxygen species; once active it phosphorylates a wide array of substrates—including p73, TAp63, YAP (Y357), α-synuclein (Y39), PARIS (Y137), RAD51 (Y315), Dok1 (Y361), WAVE3, Lamellipodin, PARP1 (Y829), GSK3β (Y216), TFEB, and MAVS—to regulate DNA damage-induced apoptosis and cell-cycle arrest (via p53/p21), actin cytoskeletal remodeling and cell migration, autophagy-lysosomal function, innate immune signaling, and neurodegeneration; activated c-Abl is downregulated by ubiquitin-proteasome-mediated degradation, and its kinase activity is directly inhibited by F-actin binding to its C-terminal domain.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABL1 (c-Abl) is a non-receptor tyrosine kinase that integrates DNA-damage, adhesion, oxidative-stress and inflammatory signals into phosphorylation of substrates governing apoptosis, cell-cycle arrest, actin remodeling, autophagy-lysosomal function and neurodegeneration [#9, #10, #19]. Its catalytic activity is autoinhibited by an intramolecular clamp: the N-terminal myristoyl group of c-Abl 1b docks into the kinase domain to stabilize SH2/SH3 packing in a Src-like inactive assembly, and the N-terminal cap region is required for this autoinhibition such that its loss deregulates the kinase as in BCR-ABL [#0, #2]. Activation is achieved by displacement of this myristoyl/phosphotyrosine switch through phosphotyrosine ligands, a mechanism exploited therapeutically by the allosteric myristoyl-pocket inhibitor asciminib [#1, #39]. In the DNA-damage response, c-Abl is activated by the upstream kinases ATM and DNA-PK, which bind it constitutively via its SH3 domain and are required for radiation-induced c-Abl activity [#4, #5]; once active it drives p53-dependent G1 arrest through p21 induction and Cdk2 downregulation, and p53-independent apoptosis via tyrosine phosphorylation of the p53-family members p73 and TAp63 [#9, #10, #3, #11]. A second major output is actin-cytoskeletal control downstream of integrin adhesion and growth-factor signaling, where adhesion to fibronectin recruits and reactivates c-Abl and F-actin binding to its C-terminal domain directly inhibits the kinase, while active c-Abl phosphorylates WAVE3, Dok1, Lamellipodin and cortactin to drive lamellipodia, filopodia and migration [#7, #8, #13, #14, #20, #43]. c-Abl also restrains the autophagy-lysosomal pathway by phosphorylating TFEB and activating GSK3β to block TFEB nuclear translocation [#34, #35], and it acts in innate immune and inflammatory signaling through MAVS and PARP1 [#28, #27]. In neurodegeneration, c-Abl phosphorylates α-synuclein at Y39 to enhance aggregation and phosphorylates PARIS at Y137 to drive p53-dependent dopaminergic neuron loss [#19, #36]. Active c-Abl is itself turned over by ubiquitin-proteasome-mediated degradation [#16], and c-Abl is required for normal cardiac development and spermatogenesis [#37, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that c-Abl is a nuclear protein with intrinsic sequence-specific DNA-binding activity, distinguishing its normal localization from the cytoplasmic, transforming BCR-ABL form.\",\n      \"evidence\": \"EMSA, UV cross-linking and Southwestern blot identifying c-Abl in an EP enhancer complex\",\n      \"pmids\": [\"1591775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of direct DNA binding for transcription not resolved\", \"No structural basis for the DNA contact defined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the first concrete substrate mechanism, showing c-Abl uses its SH3 domain to engage and phosphorylate Crk, converting a substrate phosphorylation into an intramolecular regulatory switch.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP and Y221 mutagenesis in cells\",\n      \"pmids\": [\"8194526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological pathway context of Crk regulation not established here\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linked c-Abl activity to cell-cycle control by showing it is required for radiation-induced G1 arrest via p53-dependent, p21-dependent Cdk2 downregulation.\",\n      \"evidence\": \"Dominant-negative and knockout cells, Cdk2 kinase assays, p53/p21-null epistasis\",\n      \"pmids\": [\"8717045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct c-Abl substrate driving p21 induction not identified\", \"Mechanism connecting kinase to p53 pathway left open\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Connected c-Abl regulation to integrin adhesion, showing adhesion controls its nucleocytoplasmic distribution and reactivation.\",\n      \"evidence\": \"Cell fractionation, kinase assays and immunofluorescence of focal contacts under adhesion/detachment\",\n      \"pmids\": [\"8986783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger coupling adhesion to kinase reactivation not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified ATM and DNA-PK as the upstream activators coupling c-Abl to DNA damage, with both binding c-Abl constitutively and being required for radiation-induced activation.\",\n      \"evidence\": \"Co-IP, domain mapping, in vitro kinase reconstitution, and ATM-null/DNA-PK-deficient cells\",\n      \"pmids\": [\"9168117\", \"9109492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise activating phosphosites on c-Abl not fully mapped\", \"Quantitative contribution of each kinase in vivo unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Established c-Abl kinase activity as required for DNA damage-induced apoptosis, partly independent of p53.\",\n      \"evidence\": \"Kinase-inactive stable lines, c-abl knockout cells and clonogenic survival assays\",\n      \"pmids\": [\"9037071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proapoptotic effectors downstream of c-Abl not all defined here\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified p73 as a direct apoptotic effector, with SH3-mediated binding and tyrosine phosphorylation required for p73-dependent, radiation-enhanced apoptosis.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro kinase, kinase-dead mutants and gamma-irradiation\",\n      \"pmids\": [\"10391250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of p73 versus other apoptotic outputs unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed c-Abl kinase activity is directly negatively regulated by F-actin binding through its C-terminal motif, linking cytoskeletal state to enzymatic output.\",\n      \"evidence\": \"In vitro kinase assay with purified c-Abl and F-actin plus F-actin-binding-domain mutants\",\n      \"pmids\": [\"11309382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of F-actin-mediated inhibition not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that activated c-Abl is degraded by ubiquitin-proteasome turnover, establishing a feedback that limits active kinase levels.\",\n      \"evidence\": \"Proteasome inhibitor rescue and in vivo ubiquitination of active versus kinase-dead c-Abl\",\n      \"pmids\": [\"11719217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible E3 ligase not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the N-terminal cap as a structural autoinhibitory element whose loss deregulates the kinase and contributes to BCR-ABL oncogenesis.\",\n      \"evidence\": \"In vitro kinase assays with truncation mutants and transformation assays\",\n      \"pmids\": [\"11832214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level mechanism awaited later structural work\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the structural basis of autoinhibition, showing the myristoyl group docks into the kinase domain to lock SH2/SH3 in a Src-like inactive assembly, and defined the myristoyl/phosphotyrosine activating switch.\",\n      \"evidence\": \"X-ray crystallography plus purified-protein activity assays and mutagenesis (two coordinated Cell papers)\",\n      \"pmids\": [\"12654251\", \"12654250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of switch displacement in cells not directly visualized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended c-Abl's cytoskeletal role to filopodia formation through a Dok1-Nck pathway with demonstrated mutual genetic dependence.\",\n      \"evidence\": \"Substrate identification, Y361 mutagenesis, Co-IP and knockout fibroblast rescue\",\n      \"pmids\": [\"15148308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activation cue for spreading-induced c-Abl not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Generalized the p53-family apoptotic axis to TAp63, with therapeutic relevance to chemotherapy-induced oocyte death.\",\n      \"evidence\": \"In vitro kinase, phospho-detection, imatinib in cells and mouse oocytes, promoter assays\",\n      \"pmids\": [\"19783996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific p63 phosphosites and stability mechanism partly undefined here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed c-Abl directly on chromatin in the DNA-damage response by phosphorylating RAD51 at Y315 to promote stable chromatin association.\",\n      \"evidence\": \"Chromatin fractionation, in vitro kinase and RAD51 oligomerization mutants\",\n      \"pmids\": [\"19285032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation insufficient to restore oligomerization\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified YAP-Y357 as a c-Abl substrate that inactivates YAP oncogenic transcriptional output, revealing a tumor-suppressive arm of c-Abl signaling.\",\n      \"evidence\": \"Y357F/E mutagenesis, TEAD reporter and endogenous target genes, transformation/migration assays\",\n      \"pmids\": [\"25361080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of tumor-suppressive YAP regulation with oncogenic BCR-ABL not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established c-Abl as a driver of α-synuclein pathology, phosphorylating Y39 to enhance aggregation, with in vivo and human-tissue validation.\",\n      \"evidence\": \"In vitro kinase, phospho-antibody, c-Abl gain/loss in transgenic mice, aggregation assays, PD postmortem tissue\",\n      \"pmids\": [\"27348587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Y39 phosphorylation promotes aggregation not structurally defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified c-Abl as a negative regulator of the autophagy-lysosomal pathway, acting through GSK3β-Y216 activation to block TFEB nuclear translocation.\",\n      \"evidence\": \"Co-IP, in vitro kinase at Y216, GSK3β knockdown and TFEB localization in MPP+ neurons\",\n      \"pmids\": [\"30165626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect TFEB regulation not separated here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed c-Abl directly tyrosine-phosphorylates TFEB to retain it in the cytoplasm independently of mTORC1, positioning c-Abl inhibition as a lysosomal-activating strategy in lysosomal storage disease.\",\n      \"evidence\": \"Phospho-tyrosine detection, c-Abl inhibition/ablation and TFEB localization in NPC cell and mouse models\",\n      \"pmids\": [\"33163944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TFEB phosphosites not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a c-Abl-PARIS-KAP1-MDM4-p53 axis driving dopaminergic neurodegeneration, supported by multiple genetic models and human tissue.\",\n      \"evidence\": \"In vitro kinase, Y137 phospho-Co-IP, PARIS/parkin mouse models and PD postmortem brain\",\n      \"pmids\": [\"34581802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability beyond parkin-deficient context not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Validated the myristoyl pocket as a druggable allosteric site, with asciminib inducing the inactive conformation and showing non-overlapping resistance with ATP-competitive inhibitors.\",\n      \"evidence\": \"Myristoyl-pocket binding assays, cellular potency, resistance barcoding and CML xenografts\",\n      \"pmids\": [\"28329763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term combination durability in patients beyond xenograft models not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse activating inputs (DNA damage, adhesion, ROS, inflammation) are integrated to select among the many substrate-defined outputs—apoptotic, cytoskeletal, lysosomal, immune, neurodegenerative—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of input-to-output substrate selection\", \"Relative weighting of nuclear versus cytoplasmic substrate pools unclear\", \"E3 ligase governing active-c-Abl turnover unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 6, 9, 13, 14, 19, 24, 36]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 6, 14, 19, 25, 27, 34]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 18, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [25, 38]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 5, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [34, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 13, 24, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 27, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 36, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATM\", \"DNA-PK\", \"p73\", \"CRK\", \"BRCA1\", \"GSK3B\", \"MAVS\", \"YAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}