Affinage

ABL1

Tyrosine-protein kinase ABL1 · UniProt P00519

Length
1130 aa
Mass
122.9 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 Medium

    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

    PMID:1591775

    Open questions at the time
    • Functional significance of direct DNA binding for transcription not resolved
    • No structural basis for the DNA contact defined
  2. 1994 High

    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

    PMID:8194526

    Open questions at the time
    • Physiological pathway context of Crk regulation not established here
  3. 1996 High

    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

    PMID:8717045

    Open questions at the time
    • Direct c-Abl substrate driving p21 induction not identified
    • Mechanism connecting kinase to p53 pathway left open
  4. 1996 High

    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

    PMID:8986783

    Open questions at the time
    • Molecular trigger coupling adhesion to kinase reactivation not defined
  5. 1997 High

    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

    PMID:9109492 PMID:9168117

    Open questions at the time
    • Precise activating phosphosites on c-Abl not fully mapped
    • Quantitative contribution of each kinase in vivo unresolved
  6. 1997 High

    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

    PMID:9037071

    Open questions at the time
    • Proapoptotic effectors downstream of c-Abl not all defined here
  7. 1999 High

    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

    PMID:10391250

    Open questions at the time
    • Relative contribution of p73 versus other apoptotic outputs unclear
  8. 2001 High

    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

    PMID:11309382

    Open questions at the time
    • Structural mechanism of F-actin-mediated inhibition not resolved
  9. 2001 Medium

    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

    PMID:11719217

    Open questions at the time
    • Responsible E3 ligase not identified
    • Single lab
  10. 2002 High

    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

    PMID:11832214

    Open questions at the time
    • Atomic-level mechanism awaited later structural work
  11. 2003 High

    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)

    PMID:12654250 PMID:12654251

    Open questions at the time
    • Dynamics of switch displacement in cells not directly visualized
  12. 2004 High

    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

    PMID:15148308

    Open questions at the time
    • Upstream activation cue for spreading-induced c-Abl not fully defined
  13. 2009 High

    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

    PMID:19783996

    Open questions at the time
    • Specific p63 phosphosites and stability mechanism partly undefined here
  14. 2009 Medium

    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

    PMID:19285032

    Open questions at the time
    • Phosphorylation insufficient to restore oligomerization
    • Single lab
  15. 2014 Medium

    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

    PMID:25361080

    Open questions at the time
    • Reconciliation of tumor-suppressive YAP regulation with oncogenic BCR-ABL not addressed
    • Single lab
  16. 2016 High

    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

    PMID:27348587

    Open questions at the time
    • Mechanism by which Y39 phosphorylation promotes aggregation not structurally defined
  17. 2018 Medium

    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

    PMID:30165626

    Open questions at the time
    • Direct versus indirect TFEB regulation not separated here
    • Single lab
  18. 2020 Medium

    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

    PMID:33163944

    Open questions at the time
    • TFEB phosphosites not mapped
    • Single lab
  19. 2021 High

    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

    PMID:34581802

    Open questions at the time
    • Generalizability beyond parkin-deficient context not tested here
  20. 2017 High

    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

    PMID:28329763

    Open questions at the time
    • Long-term combination durability in patients beyond xenograft models not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140096 catalytic activity, acting on a protein 8 GO:0008092 cytoskeletal protein binding 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3 R-HSA-9612973 Autophagy 2
Partners
ATMBRCA1CRKDNA-PKGSK3BMAVSP73YAP1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. X-ray crystallography of c-Abl protein Cell High 12654251
2003 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. Biochemical activity assays of purified c-Abl combined with structural analysis and mutagenesis Cell High 12654250
2002 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. In vitro kinase activity assay with purified c-Abl truncation mutants; oncogenic transformation assay Cell High 11832214
1999 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. Co-immunoprecipitation, in vitro kinase assay, transient transfection with kinase-dead mutants, gamma-irradiation of cells Nature High 10391250
1997 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. Co-immunoprecipitation, kinase activity assays in AT cells vs. control cells, domain-mapping studies Nature High 9168117
1997 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. Co-immunoprecipitation, in vitro kinase assay, DNA-PK-deficient cell lines, irradiation experiments Nature High 9109492
1994 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. In vitro kinase assay, Co-immunoprecipitation, site-directed mutagenesis (Y221) The EMBO Journal High 8194526
1996 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. Cell fractionation, kinase activity assays, immunofluorescence microscopy of focal contacts, integrin-mediated adhesion assays PNAS High 8986783
2001 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. In vitro kinase assay with purified c-Abl and F-actin, mutagenesis of F-actin binding domain, kinase activity in detached cells Journal of Biological Chemistry High 11309382
1996 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. 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 Nature High 8717045
1997 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. Stable expression of wild-type vs. kinase-inactive c-Abl, c-abl knockout cells, clonogenic survival assays, apoptosis measurement PNAS High 9037071
2009 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. In vitro kinase assay, phospho-specific detection, imatinib treatment in cell lines and mouse oocytes, promoter activation assays Nature Medicine High 19783996
2000 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. Kinase activity assays in cells treated with H2O2, cytochrome c release assays, c-Abl-deficient cells Journal of Biological Chemistry Medium 10770918
2007 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. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, imatinib inhibition, lamellipodia/migration assays Journal of Biological Chemistry Medium 17623672
2004 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. Unbiased substrate identification, in vitro kinase assay, site-directed mutagenesis (Y361), Co-immunoprecipitation, knockout fibroblasts, filopodia quantification Journal of Cell Biology High 15148308
2001 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. SH3 domain binding screen, Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, Abl-/- mouse fibroblasts, STI571 inhibition Journal of Biological Chemistry Medium 11390389
2001 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. Proteasome inhibitor treatment, ubiquitination assays, comparison of wild-type vs. activated vs. kinase-dead c-Abl stability Current Biology Medium 11719217
2002 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. Co-immunoprecipitation, in vitro kinase assay, domain mapping (PXXP/SH3), ATM-deficient cells, irradiation experiments Molecular and Cellular Biology Medium 12024016
1992 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. Gel retardation/EMSA, UV cross-linking, Southwestern blot, immunological identification of c-Abl in the complex Cell Medium 1591775
2016 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. In vitro kinase assay, phospho-specific antibody, c-Abl knockout and overexpression in transgenic mice, α-synuclein aggregation assay, human postmortem tissue analysis Journal of Clinical Investigation High 27348587
2010 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. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, rescue experiments, PDGF/netrin-1 stimulation, neuronal culture Current Biology Medium 20417104
2008 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. Kinase inhibitors, RNAi knockdown, conditional knockout mice (T-cell specific), actin polymerization assays, Co-immunoprecipitation (SH2-phospho-HS1) Blood High 18305217
2003 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. Nuclear matrix fractionation, phospho-specific detection, STI-571 inhibition, c-Abl-defective cell lines, baculovirus co-expression Journal of Biological Chemistry Medium 12824179
2012 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. In vitro kinase assay, immunoblotting, Co-immunoprecipitation (MST2-Raf-1 disruption), cell death assay PLoS ONE Medium 22590567
2014 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. Reporter assays, phospho-specific antibody, site-directed mutagenesis (Y357F/E), cell transformation, migration and anchorage-independent growth assays, endogenous TEAD target gene analysis Cell Death and Differentiation Medium 25361080
2009 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. Chromatin fractionation, in vitro kinase assay, RAD51 oligomerization-defective mutants, phospho-Y315 specific readout Biochemical and Biophysical Research Communications Medium 19285032
2010 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. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y79/Y118), STI571 treatment, Abl-null cells, lysosomal degradation assays Cell Death and Differentiation Medium 20150913
2019 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. Co-immunoprecipitation, in vitro kinase assay, phospho-specific detection, c-Abl nuclear translocation assay, NF-κB reporter, siRNA knockdown, in vivo LPS model Journal of Immunology Medium 31399520
2010 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. Co-immunoprecipitation (in vivo and in vitro), phosphotyrosine-specific antibody, c-Abl knockdown (siRNA), IFN and NF-κB reporter assays FEBS Letters Medium 19914245
2006 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. Co-immunoprecipitation, in vitro binding assay with deletion mutants, kinase activity assay, ionizing radiation treatment Cancer Research Medium 16397227
2002 c-Abl phosphorylates Bruton's tyrosine kinase (Btk) at tyrosine 223 within the Btk SH3 domain. c-Abl and Btk physically interact. Co-immunoprecipitation, in vitro kinase assay with site identification Biochemical and Biophysical Research Communications Low 12445832
2008 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. STI571 inhibition, stable shRNA knockdown of c-Abl/p73α/GADD45α, p53 loss-of-function approaches, apoptosis assays Journal of Biological Chemistry Medium 18480060
2010 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. Mass spectrometry (site identification in vitro and in vivo), co-immunoprecipitation (ΔNp63α–YAP), siRNA knockdown, rescue experiments, cisplatin treatment Cell Death & Disease Medium 21364617
2019 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. Phospho-specific antibody, c-Abl inhibitor treatment, integrin α5β1 blocking peptide, Apoe-/- mouse atherosclerosis model, mechanistic cell studies Journal of Clinical Investigation Medium 30629551
2018 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+. Co-immunoprecipitation, in vitro kinase assay (Y216), siRNA knockdown of GSK3β, TFEB localization assay, c-Abl activator/inhibitor treatments Toxicological Sciences Medium 30165626
2020 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. TFEB nuclear translocation assay, phospho-tyrosine detection, c-Abl inhibition and genetic ablation, lysosomal biogenesis/autophagy assays, NPC cell and mouse models iScience Medium 33163944
2021 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. 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 Brain High 34581802
2009 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. c-Abl knockout mouse phenotyping, cardiomyocyte-specific c-Abl rescue via transgene, histology, cell cycle gene expression analysis PNAS High 20080568
1998 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. Immunolocalization on meiotic chromosomes, c-Abl knockout mouse analysis of testis phenotype Oncogene Medium 9583675
2017 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. Biochemical binding assays (myristoyl pocket), cellular potency assays, genetic barcoding for resistance, mouse CML xenograft model Nature High 28329763
2003 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. Co-immunoprecipitation in COS cells, in vitro binding assay, kinase-dead and N-terminal deletion mutants Cancer Research Low 12591740
2021 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. Co-immunoprecipitation, phospho-tyrosine detection on RIPK3, imatinib treatment, genetic c-Abl ablation in GD cell and mouse models Biochimica et Biophysica Acta Medium 33549745
2016 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. Imatinib treatment, c-Abl re-expression rescue, immunofluorescence microscopy, lysosome inhibitors, pharmacological Hsc70 inhibition Journal of Biological Chemistry Medium 27226592
2014 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. RNAi knockdown, time-lapse microscopy, phospho-cortactin antibody, Co-IP (cortactin-Pfn-1), cell-permeable peptide to disrupt cortactin-Pfn-1, β1-integrin blocking American Journal of Physiology – Cell Physiology Medium 24477238
2018 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. Co-immunoprecipitation with domain mutants, cytochalasin D cytoskeletal disruption rescue assay, CD16/7-nephrin chimeric construct Cell Death & Disease Low 29416010

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell 704 12654251
2008 Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 547 18827185
1999 Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 496 10391250
2017 The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature 469 28329763
1997 Interaction between ATM protein and c-Abl in response to DNA damage. Nature 410 9168117
2004 Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nature reviews. Molecular cell biology 394 14708008
2003 A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 384 12654250
2020 Response and Resistance to BCR-ABL1-Targeted Therapies. Cancer cell 351 32289275
1994 c-Abl kinase regulates the protein binding activity of c-Crk. The EMBO journal 349 8194526
2009 Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nature medicine 281 19783996
1996 Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proceedings of the National Academy of Sciences of the United States of America 270 8986783
1999 Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends in cell biology 258 10322452
1997 Functional interaction between DNA-PK and c-Abl in response to DNA damage. Nature 224 9109492
1996 Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature 223 8717045
2017 The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Science translational medicine 200 28539470
2002 Autoinhibition of c-Abl. Cell 195 11832214
1984 The mouse c-abl locus: molecular cloning and characterization. Cell 191 6319018
1997 Regulation of DNA damage-induced apoptosis by the c-Abl tyrosine kinase. Proceedings of the National Academy of Sciences of the United States of America 166 9037071
2016 Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. The Journal of clinical investigation 151 27348587
1998 Determination of cell fate by c-Abl activation in the response to DNA damage. Oncogene 150 9916993
2000 Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species. The Journal of biological chemistry 144 10770918
2000 c-Abl: activation and nuclear targets. Cell death and differentiation 118 10713716
2008 Cytoplasmic signalling by the c-Abl tyrosine kinase in normal and cancer cells. Biology of the cell 116 18851712
2019 c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow. The Journal of clinical investigation 115 30629551
2011 c-Abl in neurodegenerative disease. Journal of molecular neuroscience : MN 107 21728062
2011 BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance. Journal of hematology & oncology 104 21299849
2001 Inhibition of c-Abl tyrosine kinase activity by filamentous actin. The Journal of biological chemistry 93 11309382
2005 Role of c-Abl in the DNA damage stress response. Cell research 86 15686624
2011 ABL1 fusion genes in hematological malignancies: a review. European journal of haematology 84 21435002
1987 Expression of c-abl in Philadelphia-positive acute myelogenous leukemia. Blood 84 3311207
2007 c-Abl-mediated phosphorylation of WAVE3 is required for lamellipodia formation and cell migration. The Journal of biological chemistry 81 17623672
2017 c-Abl and Parkinson's Disease: Mechanisms and Therapeutic Potential. Journal of Parkinson's disease 79 29103051
2016 Characterization of leukemias with ETV6-ABL1 fusion. Haematologica 77 27229714
2011 The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm. Cancer 70 21732333
1992 c-abl has a sequence-specific enhancer binding activity. Cell 70 1591775
2010 c-Abl, Lamellipodin, and Ena/VASP proteins cooperate in dorsal ruffling of fibroblasts and axonal morphogenesis. Current biology : CB 69 20417104
2008 The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse. Blood 68 18305217
2002 Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Molecular and cellular biology 64 12024016
2004 c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. The Journal of cell biology 62 15148308
2001 c-Abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. The Journal of biological chemistry 61 11390389
2017 Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation. PLoS genetics 60 28072818
2017 Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 60 28466394
2020 α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment. Molecular neurodegeneration 59 32299471
2008 Activated c-Abl tyrosine kinase in malignant solid tumors. Oncogene 58 18391983
2014 c-Abl antagonizes the YAP oncogenic function. Cell death and differentiation 56 25361080
2018 Chronic Myeloid Leukemia: Beyond BCR-ABL1. Current hematologic malignancy reports 55 30370478
2020 Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: Emphasis on ponatinib. International journal of cardiology 53 32470534
2001 Activated c-Abl is degraded by the ubiquitin-dependent proteasome pathway. Current biology : CB 52 11719217
1993 Oncogenic activation of c-ABL by mutation within its last exon. Molecular and cellular biology 52 8336729
2012 Regulation of neuronal cell death by c-Abl-Hippo/MST2 signaling pathway. PloS one 49 22590567
2005 C-Abl as a modulator of p53. Biochemical and biophysical research communications 48 15865930
2023 Transcriptomic classes of BCR-ABL1 lymphoblastic leukemia. Nature genetics 47 37337105
2009 Chronic myelogenous leukemia, BCR-ABL1+. American journal of clinical pathology 47 19605820
2009 c-Abl tyrosine kinase regulates cardiac growth and development. Proceedings of the National Academy of Sciences of the United States of America 47 20080568
2022 Development of asciminib, a novel allosteric inhibitor of BCR-ABL1. Critical reviews in oncology/hematology 46 35021069
2010 c-Abl phosphorylation of ΔNp63α is critical for cell viability. Cell death & disease 46 21364617
2010 ABL1 rearrangements in T-cell acute lymphoblastic leukemia. Genes, chromosomes & cancer 45 20073070
1998 Functional role for the c-Abl tyrosine kinase in meiosis I. Oncogene 45 9583675
2003 c-Abl tyrosine kinase selectively regulates p73 nuclear matrix association. The Journal of biological chemistry 44 12824179
2020 c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder. iScience 41 33163944
2015 Misfolding, Aggregation, and Disordered Segments in c-Abl and p53 in Human Cancer. Frontiers in oncology 40 25973395
2012 BCR-ABL1 kinase domain mutations: methodology and clinical evaluation. American journal of hematology 40 22231203
2019 A kinase-independent role for CDK8 in BCR-ABL1+ leukemia. Nature communications 39 31628323
2016 c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson's Disease. Frontiers in aging neuroscience 39 27833551
2014 Role of c-Abl tyrosine kinase in smooth muscle cell migration. American journal of physiology. Cell physiology 39 24477238
2019 c-Abl-Mediated Tyrosine Phosphorylation of PARP1 Is Crucial for Expression of Proinflammatory Genes. Journal of immunology (Baltimore, Md. : 1950) 38 31399520
2017 BCR-ABL1-like acute lymphoblastic leukaemia: From bench to bedside. European journal of cancer (Oxford, England : 1990) 38 28709134
2015 BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene. Molecular cancer 37 26179066
2011 DNA damage response: the emerging role of c-Abl as a regulatory switch? Biochemical pharmacology 36 21763684
2017 SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 34 28804122
2010 c-Abl and Arg tyrosine kinases regulate lysosomal degradation of the oncoprotein Galectin-3. Cell death and differentiation 34 20150913
2000 c-Abl tyrosine kinase is not essential for ataxia telangiectasia mutated functions in chromosomal maintenance. The Journal of biological chemistry 34 10625600
2022 Allosteric enhancement of the BCR-Abl1 kinase inhibition activity of nilotinib by cobinding of asciminib. The Journal of biological chemistry 33 35809644
2020 ABL1, Overexpressed in Hepatocellular Carcinomas, Regulates Expression of NOTCH1 and Promotes Development of Liver Tumors in Mice. Gastroenterology 33 32171747
2018 Role of c-Abl-GSK3β Signaling in MPP+-Induced Autophagy-Lysosomal Dysfunction. Toxicological sciences : an official journal of the Society of Toxicology 33 30165626
2009 c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis. Journal of cellular physiology 33 19306298
2018 C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease. CNS & neurological disorders drug targets 31 28571531
2023 Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase. Blood research 30 36891575
2022 Allosteric regulation of autoinhibition and activation of c-Abl. Computational and structural biotechnology journal 30 36051879
2008 DNA mismatch repair-dependent activation of c-Abl/p73alpha/GADD45alpha-mediated apoptosis. The Journal of biological chemistry 30 18480060
1985 Increased expression of a novel c-abl-related RNA in K562 cells. Blood 29 2578837
2020 ABL1-Directed Inhibitors for CML: Efficacy, Resistance and Future Perspectives. Anticancer research 28 32366389
2016 The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase. The Journal of biological chemistry 28 27226592
2010 c-Abl tyrosine kinase interacts with MAVS and regulates innate immune response. FEBS letters 27 19914245
2009 c-ABL tyrosine kinase stabilizes RAD51 chromatin association. Biochemical and biophysical research communications 27 19285032
2018 Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II. Cell death & disease 26 29416010
2023 c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases. Neural regeneration research 25 35900397
2023 The Role of c-Abl Tyrosine Kinase in Brain and Its Pathologies. Cells 25 37626851
2010 DNA damage stress response in germ cells: role of c-Abl and clinical implications. Oncogene 25 20818431
2003 Homo- and hetero-oligomerization of the c-Abl kinase and Abelson-interactor-1. Cancer research 25 12591740
2002 Phosphorylation of Bruton's tyrosine kinase by c-Abl. Biochemical and biophysical research communications 25 12445832
2021 Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration. Brain : a journal of neurology 23 34581802
2009 c-Abl and insulin receptor signalling. Vitamins and hormones 23 19251035
2019 Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies. Journal of medicinal chemistry 22 30689376
2016 Somatically mutated ABL1 is an actionable and essential NSCLC survival gene. EMBO molecular medicine 22 26758680
2022 The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug. Journal of medicinal chemistry 21 35609336
2008 T cell survival and function requires the c-Abl tyrosine kinase. Cell cycle (Georgetown, Tex.) 21 19098427
2006 Physical and functional interaction between hMSH5 and c-Abl. Cancer research 21 16397227
2021 c-Abl activates RIPK3 signaling in Gaucher disease. Biochimica et biophysica acta. Molecular basis of disease 20 33549745
2016 c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression. Oncotarget 20 27626309

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