{"gene":"ABI1","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":1997,"finding":"E3B1/ABI1 was identified as a binding partner of the EPS8 SH3 domain and the ABL SH3 domain in vitro, and associates with EPS8 in vivo; the protein exists as multiple phosphoserine-containing isoforms (65, 68, 72 kDa) whose hyperphosphorylation is induced by EGF stimulation.","method":"SH3-domain library screen, in vitro binding assay, in vivo co-immunoprecipitation, phosphatase digestion and phosphoamino acid analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding, single lab, two orthogonal methods","pmids":["9010225"],"is_preprint":false},{"year":1999,"finding":"EPS8 and E3B1/ABI1 transduce signals from Ras to Rac by forming a tri-complex with SOS-1 that exhibits Rac-specific GEF activity in vitro, placing ABI1 as an essential scaffold in the Ras→Rac signaling axis.","method":"In vivo co-immunoprecipitation, in vitro Rac-GEF activity assay, epistatic signaling analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of GEF activity with defined complex, replicated across multiple methods and independently followed up","pmids":["10499589"],"is_preprint":false},{"year":1998,"finding":"ABI1 (human ABI-1) was identified as a fusion partner of MLL in acute myeloid leukemia with t(10;11)(p11.2;q23); the MLL-ABI1 fusion combines MLL AT-hook/DNA methyltransferase homology domains with ABI1's homeodomain homology region, polyproline stretches, and SH3 domain.","method":"RT-PCR cloning of chimeric transcripts, chromosomal localization, sequence analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural identification of fusion transcript confirmed in two independent cases","pmids":["9694699"],"is_preprint":false},{"year":2000,"finding":"Abi-1 and Abi-2 proteins are expressed in the developing nervous system, are concentrated in synaptosomes and growth cone particles, and their phosphorylation state changes with age in brain lysates, consistent with participation in Abl kinase signaling at neuronal structures.","method":"Subcellular fractionation, immunohistochemistry, Western blotting of brain lysates","journal":"Molecular and cellular neurosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by fractionation and IHC, single lab, no direct functional consequence tested","pmids":["10995551"],"is_preprint":false},{"year":2000,"finding":"ABI-1 SH3 domain interacts with ENL (an MLL fusion partner) via an internal ENL region; the interaction was confirmed by yeast two-hybrid, far-Western blot, GST pulldown, and co-immunoprecipitation.","method":"Yeast two-hybrid, far-Western blot, GST pulldown, co-immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding methods, single lab","pmids":["10777208"],"is_preprint":false},{"year":2003,"finding":"PI3K (via its p85 regulatory subunit) is recruited by ABI1 into the EPS8-ABI1-SOS1 complex; PIP3 (the PI3K catalytic product) and p85 recruitment cooperate to unmask the Rac-GEF activity of the complex in vitro and are required for Rac activation and actin remodeling in vivo.","method":"Co-immunoprecipitation, in vitro Rac-GEF assay, dominant-negative and KO cell experiments, colocalization studies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GEF reconstitution combined with cell-based loss-of-function, multiple orthogonal methods in one study","pmids":["12515821"],"is_preprint":false},{"year":2004,"finding":"ABI1 directly interacts with the WHD domain of WAVE2, stimulates WAVE2-mediated actin polymerization activity in vitro, and mediates assembly of the WAVE2-ABI1-NAP1-PIR121 complex; RNAi knockdown of ABI1 abrogates Rac-dependent lamellipodia protrusion in vivo.","method":"Tandem mass spectrometry, in vitro actin polymerization assay, co-immunoprecipitation, RNAi knockdown with live-cell imaging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of actin nucleation activity, RNAi phenotypic rescue, MS identification, multiple orthogonal methods","pmids":["15048123"],"is_preprint":false},{"year":2004,"finding":"ABI1 binds WAVE1 through an amino-terminal WAVE-binding (WAB) domain; disruption of this interaction prevents ABI1 from reaching lamellipodia tips and reduces WAVE1 protein levels in fibroblasts lacking one Abi1 allele and null for Abi2, an effect rescued by Abi1 constructs retaining WAVE1 binding. ABI1 also contains an overlapping SNARE domain that interacts with Syntaxin-1 and undergoes leptomycin B-sensitive nucleocytoplasmic shuttling.","method":"Domain mapping, rescue experiments in MEFs, co-immunoprecipitation, leptomycin B treatment, live-cell localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with functional rescue, multiple cell-based methods, single lab","pmids":["15143189"],"is_preprint":false},{"year":2005,"finding":"ABI1 binds N-WASP with nanomolar affinity and, cooperating with Cdc42, potently induces N-WASP actin polymerization activity in vitro. ABI1 and WAVE are both required for Rac-dependent membrane protrusion and macropinocytosis, whereas ABI1 and N-WASP (but not WAVE) regulate actin-based vesicular transport, EGFR endocytosis, and receptor surface distribution.","method":"In vitro actin polymerization assay, binding affinity measurements, RNAi knockdown, EGFR endocytosis assay, macropinocytosis assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with affinity measurement, RNAi loss-of-function with multiple distinct phenotypic readouts, single study with orthogonal methods","pmids":["16155590"],"is_preprint":false},{"year":2005,"finding":"Eps8 promotes actin filopodia-like structures; interaction with ABI1 modulates actin architecture toward cables and star-like structures, and the Eps8/ABI1 complex recruits N-WASP to regulate actin nucleator localization/activity.","method":"Overexpression in cultured cells and Xenopus embryos, colocalization, dominant-negative constructs","journal":"BMC cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression assays without reconstitution or clean loss-of-function rescue","pmids":["16225669"],"is_preprint":false},{"year":2005,"finding":"In response to CSF-1, WAVE2 and ABI1 form a stable complex in macrophages and are co-recruited to F-actin-rich protrusions; knockdown of either WAVE2 or ABI1 by RNAi impairs CSF-1-induced membrane protrusions and macrophage migration.","method":"Co-immunoprecipitation, RNAi knockdown, dominant-negative constructs, fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with RNAi phenotype, single lab, two methods","pmids":["16280551"],"is_preprint":false},{"year":2006,"finding":"ABI1 interacts with betaPIX (a Rac1 GEF) via its C-terminal region in vitro and via N-terminal region in vivo; co-expression of ABI1 with truncated betaPIX blocks PDGF-induced dorsal membrane ruffle formation.","method":"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, overexpression functional assay","journal":"Cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding assays with limited functional follow-up","pmids":["16940963"],"is_preprint":false},{"year":2007,"finding":"ABI1 is localized in neurites, growth cones, and later enriched in dendritic spines and PSDs. It co-immunoprecipitates with the ProSAP2/Shank3 scaffold and with Eps8/SOS1. Upon NMDA stimulation, ABI1 translocates from PSDs to nuclei in an Abl kinase-dependent manner, where it associates with Myc/Max transcription factor complex and enhances E-box-regulated gene transcription. Knockdown causes excessive dendritic branching and immature spine/synapse morphology.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, nuclear translocation assay, reporter gene assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RNAi phenotype, reporter assay, live imaging), single lab","pmids":["17304222"],"is_preprint":false},{"year":2007,"finding":"Chlamydia trachomatis infection promotes Rac interaction with WAVE2 and ABI1 (but not IRSp53) as shown by co-immunoprecipitation; siRNA depletion of WAVE2 or ABI1 abrogates chlamydia-induced actin recruitment and significantly reduces uptake.","method":"Co-immunoprecipitation, siRNA knockdown, infection assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss-of-function RNAi with defined phenotypic readout, single lab","pmids":["17501982"],"is_preprint":false},{"year":2007,"finding":"Abi-1 forms an EGF-inducible complex with the Cbl ubiquitin ligase; an Abi-1 mutant lacking the SH3 domain fails to interact with Cbl, inhibits EGFR internalization, and prevents Cbl membrane accumulation after EGF. Oncogenic Abl disrupts the EGF-inducible Abi-1/Cbl complex.","method":"Co-immunoprecipitation, dominant-negative overexpression, EGFR internalization assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain-mapping and functional internalization assay, single lab","pmids":["17395426"],"is_preprint":false},{"year":2008,"finding":"Phosphotyrosine pY213 of ABI1 allosterically inhibits nonmyristoylated c-Abl kinase in trans by concurrent binding of pY213 to the Abl SH2 domain and a proximal PXXP motif to the Abl SH3 domain; wild-type ABI1 (but not Y213F mutant) inhibits Abl pY412 autophosphorylation in vivo.","method":"In vitro kinase assay with phosphopeptides, mutagenesis (Y213F), co-expression in cells, phosphorylation assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical mechanism with mutagenesis, validated in cells with orthogonal methods","pmids":["18328268"],"is_preprint":false},{"year":2009,"finding":"In C. elegans, ABI-1 interacts with the UNC-53/NAV2 scaffolding protein via a restricted calponin homology (CH) domain of UNC-53; ABI-1 and UNC-53 share overlapping expression and similar cell-migration phenotypes, and ABI-1 links UNC-53 to the ARP2/3 complex for actin remodeling during cell migration.","method":"Yeast two-hybrid, domain mapping, phenotypic analysis of mutants, RNAi of actin-regulatory partners","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus physical interaction mapping, ortholog validated in C. elegans","pmids":["19168673"],"is_preprint":false},{"year":2010,"finding":"ABI1 isoform 3 (lacking exon 10) constitutively activates Rac1 and promotes macropinocytosis; isoform 2 (containing exon 10) preferentially binds activated Rac1 via an exon-10 site, suppresses macropinocytosis, and is more cytoplasmic. Both isoforms bind inactive Rac1 through a non-exon-10 site.","method":"Flow cytometry macropinocytosis assay, Rac1 activation assay, in vitro binding with exon-10 domain, subcellular fractionation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (flow cytometry, in vitro binding, fractionation), single lab","pmids":["20479892"],"is_preprint":false},{"year":2010,"finding":"ABI1 pY213 links Abl kinase signaling to the p85 regulatory subunit of PI3K: phosphorylation of Y213 is required for Abl to regulate macropinocytosis, and pY213 interacts with the C-terminal SH2 domain of p85.","method":"SH2 domain library screen, interaction mapping, loss-of-function Y213 mutant, macropinocytosis assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain library screen plus mutagenesis and functional assay, single lab","pmids":["20598684"],"is_preprint":false},{"year":2010,"finding":"Dysbindin-1 interacts with WAVE2 (but not N-WASP) and with ABI1, and dysbindin-1 promotes the WAVE2-ABI1 interaction; the three proteins form a ternary complex. RNAi knockdown of dysbindin-1 produces abnormally elongated immature dendritic protrusions, phenocopying ABI1 loss.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying ternary complex and RNAi phenotype, single lab","pmids":["20531346"],"is_preprint":false},{"year":2010,"finding":"Integrity of the SOS1/EPS8/ABI1 tri-complex is essential for LPA-induced Rac activation, cell migration, and peritoneal metastatic colonization of ovarian cancer cells; ABI1 acts as the scaffold holding SOS1 and EPS8 together in the complex.","method":"Co-immunoprecipitation, knockdown, re-expression rescue, in vivo metastasis assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with loss-of-function and gain-of-function rescue, in vivo confirmation, single lab","pmids":["21118970"],"is_preprint":false},{"year":2010,"finding":"Abi1 directly binds the α4 integrin cytoplasmic tail (confirmed by purified protein binding assay), colocalizes with phosphorylated α4 at the leading edge, and Abi1-deficient cells expressing α4 have impaired cell spreading rescued by wild-type but not α4-binding-deficient Abi1.","method":"Direct binding assay with purified proteins, co-localization, KO mouse, rescue with Abi1 mutant","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding with purified proteins plus KO mouse with mutant rescue, single lab, multiple orthogonal methods","pmids":["21173240"],"is_preprint":false},{"year":2011,"finding":"Abi1 knockout in mice causes embryonic lethality (~E11.5) with heart and brain malformations. Abi1-KO cells show reduced WAVE1, WAVE2, NAP1, and Sra-1/PIR121 levels, decreased migration rate and distance, and decreased dorsal ruffling, demonstrating that Abi1 is critical for WAVE complex integrity and stability.","method":"Conditional KO mouse, Western blotting, cell migration assay, ruffling assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal readouts, replicated across cell and organismal levels","pmids":["21482783"],"is_preprint":false},{"year":2011,"finding":"CDK1/cyclin B phosphorylates ABI1 at serine 216 at mitotic entry, and this phosphorylation attenuates Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex and F-actin assembly; phosphomimetic S216D mutation in ABI1 is sufficient to recapitulate this attenuation and interferes with cell cycle progression.","method":"In vitro kinase assay, phosphomimetic mutagenesis, cell cycle analysis, F-actin assembly assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay combined with phosphomimetic mutation and functional cell-cycle/actin readouts","pmids":["21900237"],"is_preprint":false},{"year":2011,"finding":"Abi1 knockdown by shRNA in Bcr-Abl-transformed cells attenuates abnormal actin remodeling, inhibits cell adhesion and migration on fibronectin, and impairs leukemogenesis in NOD/SCID mice; Abi1 silencing also attenuates Bcr-Abl-stimulated activation of Lyn (Src family kinase).","method":"shRNA knockdown, actin remodeling assay, adhesion/migration assay, in vivo leukemogenesis assay, kinase activity assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts including in vivo, single lab","pmids":["18453543"],"is_preprint":false},{"year":2011,"finding":"Abi-1 and CaMKIIα interact at resting conditions through Abi1's tSNARE domain (which has homology to CaMKIIα regulatory domain); this interaction mutually inhibits both proteins including Abi1-dependent Rac activation. Glutamate receptor activation causes calmodulin binding leading to dissociation; CaMKIIα phosphorylates Abi1 at serine 88 prior to dissociation, contributing to Rac activation and spine maturation.","method":"Co-immunoprecipitation, FRET-based activity sensors, mutagenesis, spine morphology analysis in neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with FRET-based activity measurement and mutagenesis, single lab","pmids":["22993434"],"is_preprint":false},{"year":2011,"finding":"An SK3 channel/nWASP/Abi-1 trimeric complex is present in neural stem cells and postsynaptic compartments; SK3 and nWASP act synergistically to induce filopodial outgrowth, while Abi-1 acts antagonistically to these partners to regulate neurite outgrowth.","method":"Co-immunoprecipitation, overexpression, pharmacological SK3 channel activation, fluorescence microscopy","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and overexpression only, single lab, no clean loss-of-function rescue","pmids":["21464958"],"is_preprint":false},{"year":2011,"finding":"hnRNPK interacts with the Abi-1 SH3 domain through the hnRNPK KI domain; knockdown of hnRNPK phenocopies Abi-1 knockdown (enlarged dendritic tree, increased filopodia, decreased mature synapses), indicating synergistic function in a multiprotein complex regulating spine/filopodia balance.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, fluorescence microscopy","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with knockdown phenotype, single lab, no reconstitution","pmids":["22102872"],"is_preprint":false},{"year":2012,"finding":"C. elegans ABI-1 SH3 domain directly binds MIG-10 (lamellipodin); epistasis analysis places ABI-1 and WVE-1 downstream of MIG-10 to mediate axon guidance in both UNC-6 (netrin) and SLT-1 (slit) pathways; this ABI-1/MIG-10 interaction also promotes lamellipodia formation in cultured mammalian cells.","method":"Yeast two-hybrid, co-immunoprecipitation, domain mapping, epistasis analysis, cell-based lamellipodia assay","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus physical interaction with cross-species validation, single lab","pmids":["23209429"],"is_preprint":false},{"year":2012,"finding":"MIG-10B isoform interacts with ABI-1 to organize the actin cytoskeleton at presynaptic sites and instruct synaptic vesicle clustering through Synapsin-1 (SNN-1) downstream of Netrin; a dominant-negative MIG-10B construct expressing a specific N-terminal domain disrupts vesicle clustering and thermotaxis behavior in vivo.","method":"Genetic analysis, domain mapping, dominant-negative construct, in vivo behavioral assay","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with dominant-negative construct, single lab","pmids":["23028145"],"is_preprint":false},{"year":2013,"finding":"Stimulation with acetylcholine induces Abi1 association with N-WASP in smooth muscle; Abi1 knockdown inhibits N-WASP activation, actin polymerization, and contraction without affecting myosin light chain phosphorylation. A multiprotein complex of c-Abl, CAS, and Abi1 forms upon contractile activation, and Abi1 is activated by c-Abl/CAS while Abi1 reciprocally controls c-Abl activation (pY412) and CAS interaction.","method":"Co-immunoprecipitation, lentiviral RNAi, FRET-based N-WASP sensor, actin polymerization assay, contraction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — FRET sensor for activity, reconstitution of multi-protein complex, RNAi with multiple orthogonal functional readouts, single lab","pmids":["23740246"],"is_preprint":false},{"year":2014,"finding":"Y435-phosphorylated ABI1 localizes at sites of extracellular matrix degradation in colorectal carcinoma cells; RNAi knockdown of ABI1 suppresses matrix dissolution by 95%, and STI571 treatment abolishes ABI1 Y435-phosphorylation and suppresses matrix degradation, fibronectin attachment, and cell invasion.","method":"RNAi knockdown, matrix degradation assay, STI571 kinase inhibitor treatment, immunofluorescence","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function and pharmacological inhibition with quantitative functional assays, single lab","pmids":["24913355"],"is_preprint":false},{"year":2010,"finding":"Activated Rac1 specifically binds to a site encoded by exon 10 in ABI1 isoform 2 in vitro; because exon 10 is absent in isoform 3 due to alternative splicing, the isoform-2 WAVE2 complex and isoform-3 WAVE2 complex display differential binding to activated versus inactive Rac1.","method":"In vitro binding assay with activated/inactive Rac1, domain mapping by exon exclusion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with domain evidence, single lab","pmids":["20479892"],"is_preprint":false},{"year":2015,"finding":"ABI1 acts as a scaffold protein in the SOS1/EPS8/ABI1 tri-complex: the SH3 domain of ABI1 mediates SOS1 binding, and the poly-proline+PxxDY region mediates EPS8 binding; TAT-conjugated inhibitory peptides disrupting ABI1-EPS8 interaction suppress ovarian cancer invasion and metastasis in vivo.","method":"Co-immunoprecipitation, GST pulldown, domain deletion mapping, in vivo peritoneal metastasis assay with inhibitory peptides","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping plus in vivo functional validation with peptide inhibitors, single lab","pmids":["31488087"],"is_preprint":false},{"year":2015,"finding":"ABI1 bridges c-Abl and WAVE2: a linker region between the proline-rich and SH3 domains of ABI1 is required for c-Abl interaction and c-Abl-mediated WAVE2 phosphorylation; the NESH/Abi-3-based WAVE2 complex, lacking this c-Abl-binding linker, is unable to generate lamellipodial protrusions and instead may promote invadopodia.","method":"Domain deletion analysis, co-immunoprecipitation, imatinib/siRNA knockdown, morphological assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with functional phenotypic readouts, single lab","pmids":["26428302"],"is_preprint":false},{"year":2018,"finding":"Bone marrow-specific deletion of Abi1 in mice results in an MPN-like phenotype with increased activity of Src family kinases (SFKs), STAT3, and NF-κB signaling, impaired hematopoietic stem cell self-renewal, and features resembling human myelofibrosis; ABI1 thus negatively regulates SFK/STAT3/NF-κB signaling in hematopoietic cells.","method":"Conditional KO mouse, bone marrow transplantation, kinase activity assays, signaling pathway analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with competitive transplantation, multiple signaling pathway readouts, corroborated in patient samples","pmids":["30213875"],"is_preprint":false},{"year":2019,"finding":"ABI1 loss in benign prostate epithelial cells induces EMT and activation of non-canonical WNT signaling; FYN SH2 domain interacts with ABI1 pY421 (high-affinity), and ABI1 loss leads to increased STAT3 phosphorylation downstream of FZD2, suggesting ABI1 inhibits EMT through suppressing FYN-STAT3 activation.","method":"CRISPR/Cas9 gene disruption, RNA sequencing, Western blotting, SH2-ABI1 interaction assay","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with RNA-seq pathway analysis and protein interaction, single lab","pmids":["31530281"],"is_preprint":false},{"year":2020,"finding":"PTEN dephosphorylates ABI1 at Y213 and S216 (identified by phosphotyrosine immunoprecipitation/MS), leading to ABI1 degradation through the calpain pathway; this down-regulates the WAVE regulatory complex, reorganizes the actin cytoskeleton, and is required for epiblast epithelial polarization.","method":"Phosphotyrosine IP/mass spectrometry, PTEN mutant reconstitution in embryoid bodies, calpain inhibitor rescue, embryoid body polarization assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — MS-based substrate identification, PTEN mutant reconstitution, pathway rescue with calpain inhibitor, single lab with multiple orthogonal methods","pmids":["32673396"],"is_preprint":false},{"year":2020,"finding":"PTEN's protein phosphatase activity dephosphorylates and downregulates ABI1 in breast cancer cells; gain- and loss-of-function of ABI1 demonstrates that ABI1 mediates PTEN-loss-induced EMT and cancer stem cell activity.","method":"PTEN reconstitution (WT vs. mutant), gain/loss-of-function of ABI1, EMT marker analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTEN mutant analysis with ABI1 gain/loss-of-function rescue, single lab","pmids":["32728066"],"is_preprint":false},{"year":2020,"finding":"ABI1 localizes to the tip of lamellipodia and its protrusion coordinates with F-actin at the leading edge; ABI1 knockdown reduces smooth muscle cell migration and decreases leading-edge recruitment of profilin-1 (Pfn-1, identified as a new ABI1 partner), c-Abl, and N-WASP but not pVASP, cortactin, or vinculin. Integrin β1 and c-Abl regulate ABI1 positioning at the leading edge.","method":"shRNA knockdown/rescue, live-cell imaging, co-immunoprecipitation, leading-edge protein localization assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with multiple protein localization readouts and Co-IP for new binding partner, single lab","pmids":["32606387"],"is_preprint":false},{"year":2011,"finding":"Y398 in the SH3 domain of Abi-1 is a new phosphorylation site; combined disruption of Y213 and Y398 significantly weakens Abi-1 binding to c-Abl (SH3-Abl proline-rich domain interaction); Abi-1 phosphorylation at both sites stimulates Mena phosphorylation through c-Abl kinase activation.","method":"Mutagenesis, in vitro kinase assay, binding assay, phosphorylation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, single lab, limited replication","pmids":["21320496"],"is_preprint":false},{"year":2004,"finding":"E3B1/ABI1 levels are regulated by the Ca2+-activated protease calpain; serum starvation activates calpain-dependent E3B1 degradation, which is prevented by constitutively active PAK1 or by Rac1 activation downstream of PDGF; conversely, PAK auto-inhibitory domain expression causes E3B1 degradation even in serum.","method":"Calpain inhibitor treatment, constitutively active/dominant-negative constructs, Western blotting","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological and overexpression approaches, single lab, no direct reconstitution","pmids":["15178460"],"is_preprint":false},{"year":2012,"finding":"Abi1 mediates airway smooth muscle (ASM) cell proliferation by regulating JAK2 and STAT3 activation; Abi1 knockdown reduces JAK2 and STAT3 activation and ASM proliferation.","method":"shRNA loss-of-function, kinase/STAT3 phosphorylation assay, proliferation assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with kinase/transcription factor readout and proliferation assay, single lab","pmids":["35198891"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9 knockout of Abi1 in Bcr-Abl-transformed hematopoietic cells reduces ERK and PI3K/Akt signaling, inhibits IL3-independent growth and SDF-1α-mediated chemotaxis, abrogates abnormal actin remodeling, and abolishes leukemogenesis in syngeneic mice.","method":"CRISPR/Cas9 KO, signaling pathway analysis, in vivo leukemogenesis assay","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple signaling readouts and in vivo confirmation, single lab","pmids":["32276588"],"is_preprint":false},{"year":2013,"finding":"Xenopus Abi1 knockdown by morpholino disrupts eye morphogenesis; the SH3 domain of Abi1 is required for proper retinal progenitor cell movement and differentiation, and this requires an interaction with WASP (Wiskott-Aldrich syndrome protein).","method":"Morpholino knockdown, SH3 domain rescue constructs, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with domain-specific rescue, in vivo Xenopus model","pmids":["23558677"],"is_preprint":false},{"year":2021,"finding":"Loss of MBNL1 promotes expression of the Abi1-Δe10 splice isoform (lacking exon 10); Abi1-Δe10 activates Rac1 independently of upstream stimulation and triggers the Rac1-NOX1-ROS pathway leading to KLF4 upregulation, VSMC macrophage-like transdifferentiation, increased proliferation and migration.","method":"MBNL1 knockdown, splice isoform expression analysis, Rac1 activation assay, NOX1-ROS pathway analysis, VSMC phenotyping","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splice isoform-specific functional assays with pathway analysis, single lab","pmids":["33759281"],"is_preprint":false},{"year":2024,"finding":"Caskin2 associates with the WAVE regulatory complex in an ABI1-dependent manner to promote cell migration; growth factor-induced phosphorylation of Caskin2 at serine 878 regulates the Caskin2-ABI1 interaction.","method":"Co-immunoprecipitation, phospho-mutant analysis, cell migration assay","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with phosphomutant, single lab, limited mechanistic depth for ABI1 specifically","pmids":["38587458"],"is_preprint":false},{"year":2026,"finding":"During Listeria monocytogenes infection, the pore-forming toxin LLO triggers Ca2+ influx leading to calpain-mediated spectrin cleavage; this mobilizes ABI1 from its spectrin-bound cortical state, allowing ABI1 to bind EPS8 within protrusions and activate EPS8's actin-capping activity to enable actin recycling and protrusion elongation for cell-to-cell spread. Conditional Abi1 KO mice show significantly reduced Lm infection susceptibility.","method":"Conditional KO mouse, co-immunoprecipitation, calpain inhibitor assay, Ca2+ imaging, protrusion/spread assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with multiple biochemical and cell biological readouts defining molecular mechanism, multiple orthogonal methods","pmids":["41974702"],"is_preprint":false},{"year":2024,"finding":"ABI1 is imported to the plant cell nucleus by SAD2 (an importin β family protein) upon coronatine (COR) treatment; nuclear ABI1 accumulation requires SAD2 and enables COR to antagonize ABA signaling and reopen stomata during bacterial pathogen invasion.","method":"Subcellular localization assay, sad2 mutant analysis, COR treatment, stomatal aperture assay","journal":"The Plant journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization assay tied to functional stomatal phenotype in sad2 mutant, single lab","pmids":["38683723"],"is_preprint":false},{"year":2020,"finding":"CaMKIIα phosphorylates Shank3 at Ser685; this phosphorylation significantly increases binding of ABI1 to Shank3 in vitro (pre-phosphorylated GST-Shank3), whereas Ser685Ala or Ser685Asp mutation reduces ABI1-Shank3 co-immunoprecipitation from cells.","method":"In vitro kinase assay with purified CaMKIIα, co-immunoprecipitation, mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation assay with mutagenesis, single lab","pmids":["31983435"],"is_preprint":false},{"year":2024,"finding":"ABI1 degradation through ubiquitination by the E3 ligase CBLC activates ERK signaling in colorectal cancer; ABI1 upregulation abolishes the pro-tumorigenic effects of CBLC.","method":"Ubiquitination assay, co-immunoprecipitation, gain/loss-of-function, ERK pathway analysis, xenograft assay","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay combined with gain/loss-of-function rescue and in vivo model, single lab","pmids":["38743987"],"is_preprint":false}],"current_model":"ABI1 (Abelson interactor 1/E3B1) functions as a multivalent scaffold protein that (i) nucleates and maintains the WAVE regulatory complex (directly binding WAVE1/2 WHD domain) to stimulate Arp2/3-dependent actin polymerization at lamellipodia and other protrusive structures; (ii) assembles an EPS8-ABI1-SOS1 tri-complex with Rac-specific GEF activity downstream of Ras and PI3K/p85; (iii) allosterically regulates c-Abl kinase through phospho-Y213 and pY398 binding in trans to its SH2 and SH3 domains; (iv) is post-translationally regulated by CDK1 (S216 phosphorylation at mitosis), CaMKIIα (S88 phosphorylation), PTEN (Y213/S216 dephosphorylation leading to calpain-dependent degradation), and CBLC ubiquitin ligase; (v) undergoes nucleocytoplasmic shuttling and, upon synaptic stimulation, translocates to the nucleus to co-activate Myc/Max-dependent transcription; and (vi) controls smooth muscle and hematopoietic cell signaling via JAK2/STAT3 and SFK/NF-κB pathways, with loss of ABI1 causing myeloproliferative disease, EMT, and impaired epithelial morphogenesis."},"narrative":{"mechanistic_narrative":"ABI1 (Abelson interactor 1/E3B1) is a multivalent cytoskeletal scaffold that couples Rho-family GTPase and tyrosine-kinase signaling to Arp2/3-dependent actin polymerization at protrusive structures [PMID:10499589, PMID:15048123]. Its central function is to nucleate and stabilize the WAVE regulatory complex: ABI1 binds the WHD domain of WAVE2 and an N-terminal WAVE-binding domain of WAVE1 to stimulate WAVE-mediated actin polymerization and assemble the WAVE2-NAP1-PIR121 complex, and Abi1 loss in mice destabilizes WAVE1/WAVE2/NAP1/Sra-1, abolishes lamellipodial protrusion, and causes embryonic lethality with heart and brain malformations [PMID:15048123, PMID:15143189, PMID:21482783]. In parallel, ABI1 acts as the scaffold of an EPS8-ABI1-SOS1 tri-complex (SH3 domain binding SOS1, proline-rich/PxxDY region binding EPS8) that, upon recruitment of the PI3K p85 subunit and PIP3, exhibits Rac-specific GEF activity downstream of Ras to drive actin remodeling [PMID:10499589, PMID:12515821, PMID:31488087]. ABI1 also directly activates N-WASP cooperatively with Cdc42 to govern actin-based vesicular transport, EGFR endocytosis, and macropinocytosis, functions distinct from its WAVE-dependent membrane protrusion role [PMID:16155590]. ABI1 allosterically regulates c-Abl: phospho-Y213 binds the Abl SH2 domain in trans while a proximal PXXP motif engages the Abl SH3 domain, and ABI1 reciprocally bridges c-Abl to WAVE2 phosphorylation [PMID:18328268, PMID:26428302]. Its activity is gated by post-translational control including CDK1/cyclin B phosphorylation at S216 at mitosis, CaMKIIα phosphorylation at S88, and PTEN-mediated Y213/S216 dephosphorylation that triggers calpain-dependent degradation and reorganizes the actin cytoskeleton during epithelial polarization [PMID:21900237, PMID:22993434, PMID:32673396]. Alternative splicing of exon 10 produces isoforms with opposite Rac1-binding and macropinocytosis behavior [PMID:20479892]. Beyond actin, synaptically stimulated ABI1 translocates to the nucleus in an Abl-dependent manner to co-activate Myc/Max E-box transcription and shapes dendritic spine and synapse maturation [PMID:17304222]. Loss of ABI1 in hematopoietic cells causes a myeloproliferative/myelofibrosis-like disease through derepressed SFK/STAT3/NF-κB signaling, and ABI1 loss promotes EMT, while ABI1 is a fusion partner of MLL in acute myeloid leukemia [PMID:9694699, PMID:30213875, PMID:31530281].","teleology":[{"year":1997,"claim":"Established ABI1 as a phosphoprotein adaptor by showing it binds the SH3 domains of EPS8 and ABL and is hyperphosphorylated on serine after EGF stimulation, framing it as a receptor-coupled scaffold.","evidence":"SH3-domain library screen, in vitro binding and reciprocal Co-IP, phosphoamino acid analysis","pmids":["9010225"],"confidence":"Medium","gaps":["Functional consequence of EPS8/ABL binding not yet defined","Kinase driving serine hyperphosphorylation unidentified"]},{"year":1998,"claim":"Identified ABI1 as an MLL fusion partner in t(10;11) AML, linking the scaffold to leukemogenesis at the structural level.","evidence":"RT-PCR cloning of chimeric MLL-ABI1 transcripts and chromosomal mapping in patient cases","pmids":["9694699"],"confidence":"Medium","gaps":["Oncogenic mechanism of the fusion protein not tested","Contribution of ABI1 moiety vs MLL moiety unresolved"]},{"year":1999,"claim":"Showed ABI1 scaffolds an EPS8-SOS1 tri-complex with Rac-specific GEF activity, placing ABI1 mechanistically in the Ras→Rac signaling axis.","evidence":"In vivo Co-IP, in vitro Rac-GEF activity assay, epistatic signaling analysis","pmids":["10499589"],"confidence":"High","gaps":["How GEF activity is switched on in cells not yet defined","Structural basis of complex assembly unknown"]},{"year":2003,"claim":"Defined the activation input for the tri-complex by showing PI3K p85 recruitment and PIP3 unmask its Rac-GEF activity, connecting lipid signaling to actin remodeling.","evidence":"Co-IP, in vitro Rac-GEF assay, dominant-negative and KO cell experiments","pmids":["12515821"],"confidence":"High","gaps":["Quantitative stoichiometry of activation not measured","Spatial control of p85 recruitment unclear"]},{"year":2004,"claim":"Established ABI1 as a core WAVE-complex subunit by mapping direct WHD/WAB-domain binding to WAVE2/WAVE1, demonstrating it stimulates actin polymerization and is needed for lamellipodia.","evidence":"Mass spectrometry, in vitro actin polymerization assay, RNAi knockdown with live imaging, domain-mapping rescue in MEFs","pmids":["15048123","15143189"],"confidence":"High","gaps":["In vivo organismal requirement not yet tested at this stage","SNARE-domain/Syntaxin-1 functional role undefined"]},{"year":2004,"claim":"Identified calpain-dependent degradation of ABI1 controlled by Rac/PAK as a turnover mechanism, introducing proteolytic regulation of the scaffold.","evidence":"Calpain inhibitor treatment and constitutively active/dominant-negative PAK1/Rac1 constructs with Western blotting","pmids":["15178460"],"confidence":"Low","gaps":["Pharmacological/overexpression-only without reconstitution","Direct calpain cleavage site not mapped"]},{"year":2005,"claim":"Distinguished ABI1's two actin-nucleator arms by showing it directly activates N-WASP with Cdc42 for vesicular transport/EGFR endocytosis, separate from WAVE-driven membrane protrusion.","evidence":"In vitro actin polymerization with affinity measurement, RNAi with macropinocytosis and EGFR endocytosis readouts","pmids":["16155590"],"confidence":"High","gaps":["How ABI1 partitions between WAVE and N-WASP pools unknown","Regulation of nucleator choice undefined"]},{"year":2005,"claim":"Extended ABI1's actin role to physiological migration by showing CSF-1-induced WAVE2-ABI1 co-recruitment drives macrophage protrusion and motility.","evidence":"Co-IP, RNAi knockdown, dominant-negative constructs, fluorescence microscopy","pmids":["16280551"],"confidence":"Medium","gaps":["Upstream receptor-to-complex coupling not resolved"]},{"year":2007,"claim":"Revealed a nuclear/transcriptional function: synaptic NMDA stimulation drives Abl-dependent ABI1 translocation to nuclei where it co-activates Myc/Max, while it shapes dendritic spine maturation.","evidence":"Co-IP with Shank3/Eps8/SOS1, siRNA knockdown, nuclear translocation and E-box reporter assays in neurons","pmids":["17304222"],"confidence":"Medium","gaps":["Direct DNA-bound complex composition not defined","Target genes activated in vivo unknown"]},{"year":2007,"claim":"Tied ABI1 to receptor downregulation by showing an EGF-inducible Abi1-Cbl complex required for EGFR internalization, disrupted by oncogenic Abl.","evidence":"Co-IP, SH3-deletion dominant-negative, EGFR internalization assay","pmids":["17395426"],"confidence":"Medium","gaps":["Whether Cbl ubiquitinates ABI1 here not tested","Single-lab Co-IP"]},{"year":2008,"claim":"Provided the molecular mechanism by which ABI1 allosterically inhibits c-Abl, with pY213 engaging the Abl SH2 domain and a PXXP motif the SH3 domain in trans.","evidence":"In vitro kinase assays with phosphopeptides, Y213F mutagenesis, cellular co-expression","pmids":["18328268"],"confidence":"High","gaps":["Cellular kinase generating pY213 not identified in this study","Reciprocal regulation context-dependence unclear"]},{"year":2010,"claim":"Connected ABI1 tyrosine phosphorylation to lipid signaling, showing pY213 binds the p85 C-terminal SH2 domain and is required for Abl-driven macropinocytosis.","evidence":"SH2 domain library screen, Y213 mutant, macropinocytosis assay","pmids":["20598684"],"confidence":"Medium","gaps":["Direct biochemical affinity not quantified"]},{"year":2010,"claim":"Showed exon-10 alternative splicing functionally diversifies ABI1, with isoform 3 constitutively activating Rac1/macropinocytosis and isoform 2 binding activated Rac1 via the exon-10 site to suppress it.","evidence":"Macropinocytosis flow cytometry, Rac1 activation/binding assays, exon-10 domain mapping, fractionation","pmids":["20479892","20479892"],"confidence":"Medium","gaps":["Tissue-specific splicing control not defined","Structural basis of differential Rac1 binding unknown"]},{"year":2010,"claim":"Demonstrated the tri-complex is required for cancer cell invasion in vivo, with ABI1 as the obligate scaffold holding SOS1 and EPS8 for LPA-induced Rac activation and ovarian metastasis.","evidence":"Co-IP, knockdown/re-expression rescue, in vivo peritoneal metastasis assay","pmids":["21118970"],"confidence":"Medium","gaps":["Direct GEF activity in this metastatic setting not measured"]},{"year":2011,"claim":"Established ABI1 as essential for organismal development and WAVE-complex stability, with KO causing embryonic lethality and loss of WAVE/NAP1/Sra-1 protein.","evidence":"Conditional KO mouse, Western blotting, migration and ruffling assays","pmids":["21482783"],"confidence":"High","gaps":["Tissue-autonomous requirements not dissected","Mechanism stabilizing partner proteins not fully resolved"]},{"year":2011,"claim":"Introduced cell-cycle control of ABI1, showing CDK1/cyclin B phosphorylates S216 at mitosis to attenuate Bcr-Abl-driven WAVE phosphorylation and F-actin assembly.","evidence":"In vitro kinase assay, S216D phosphomimetic, cell-cycle and F-actin assays","pmids":["21900237"],"confidence":"High","gaps":["Phosphatase reversing S216 not identified here"]},{"year":2011,"claim":"Linked ABI1 to Bcr-Abl leukemogenesis, showing its knockdown reduces abnormal actin remodeling, adhesion/migration, Lyn activation, and leukemia in vivo.","evidence":"shRNA knockdown, actin/adhesion/migration assays, NOD/SCID leukemogenesis, kinase activity assay","pmids":["18453543"],"confidence":"Medium","gaps":["Direct vs indirect role in Lyn activation unresolved"]},{"year":2011,"claim":"Identified a mutually inhibitory ABI1-CaMKIIα interaction via the tSNARE domain and CaMKIIα-mediated S88 phosphorylation as a calcium-gated switch for Rac activation and spine maturation.","evidence":"Co-IP, FRET activity sensors, mutagenesis, neuronal spine morphology","pmids":["22993434"],"confidence":"Medium","gaps":["Direct biochemical demonstration of S88-driven Rac change limited"]},{"year":2011,"claim":"Mapped a second Abl-interaction tyrosine (Y398) in the SH3 domain, showing combined Y213/Y398 phosphorylation strengthens Abl binding and stimulates Mena phosphorylation.","evidence":"Mutagenesis, in vitro kinase and binding assays","pmids":["21320496"],"confidence":"Medium","gaps":["Cellular significance of dual-site phosphorylation not validated in vivo"]},{"year":2012,"claim":"Defined a conserved axon-guidance role through direct ABI-1/MIG-10 (lamellipodin) binding placing ABI-1/WAVE downstream of MIG-10 in netrin and slit pathways.","evidence":"Yeast two-hybrid, Co-IP, domain mapping, C. elegans epistasis, mammalian lamellipodia assay","pmids":["23209429","23028145"],"confidence":"Medium","gaps":["Mammalian in vivo guidance role not directly tested"]},{"year":2013,"claim":"Showed ABI1 mediates smooth muscle contraction by linking c-Abl/CAS to N-WASP activation and actin polymerization independent of myosin light chain phosphorylation.","evidence":"Co-IP, lentiviral RNAi, FRET N-WASP sensor, actin polymerization and contraction assays","pmids":["23740246"],"confidence":"High","gaps":["Order of complex assembly during contraction not fully resolved"]},{"year":2014,"claim":"Connected tyrosine-phosphorylated ABI1 (pY435) to invasion, localizing it to matrix-degradation sites in an Abl-dependent manner.","evidence":"RNAi knockdown, matrix degradation assay, STI571 treatment, immunofluorescence","pmids":["24913355"],"confidence":"Medium","gaps":["Kinase site specificity for Y435 not biochemically isolated"]},{"year":2015,"claim":"Defined how ABI1 routes the WAVE2 complex toward lamellipodia vs invadopodia, with a proline-rich/SH3 linker required for c-Abl binding and Abl-mediated WAVE2 phosphorylation.","evidence":"Domain deletion, Co-IP, imatinib/siRNA, morphological assays; tri-complex domain mapping with TAT peptides","pmids":["26428302","31488087"],"confidence":"Medium","gaps":["Switch between protrusion types not quantitatively dissected"]},{"year":2018,"claim":"Established ABI1 as a tumor-suppressive negative regulator of hematopoietic SFK/STAT3/NF-κB signaling, with bone-marrow KO producing a myeloproliferative/myelofibrosis-like disease.","evidence":"Conditional KO mouse, bone marrow transplantation, kinase and signaling assays, patient sample corroboration","pmids":["30213875"],"confidence":"High","gaps":["Direct molecular target through which ABI1 restrains SFKs unclear"]},{"year":2020,"claim":"Identified PTEN as the phosphatase that dephosphorylates ABI1 Y213/S216 to trigger calpain-dependent degradation, downregulating the WAVE complex and driving epithelial polarization and, when lost, EMT.","evidence":"Phospho-IP/MS, PTEN mutant reconstitution, calpain inhibitor rescue, embryoid body and breast cancer EMT assays","pmids":["32673396","32728066"],"confidence":"High","gaps":["Calpain cleavage site on ABI1 not mapped"]},{"year":2020,"claim":"Refined leading-edge mechanics, showing ABI1 recruits profilin-1, c-Abl and N-WASP to the lamellipodial tip under integrin β1/c-Abl control, and that CRISPR KO blocks Bcr-Abl ERK/PI3K signaling and leukemogenesis.","evidence":"shRNA/CRISPR KO, live imaging, Co-IP, leading-edge localization, in vivo leukemogenesis","pmids":["32606387","32276588"],"confidence":"Medium","gaps":["Direct profilin-1 binding interface not mapped"]},{"year":2024,"claim":"Identified ubiquitin-mediated turnover via CBLC that degrades ABI1 to activate ERK signaling in colorectal cancer, complementing calpain proteolysis as a degradation route.","evidence":"Ubiquitination assay, Co-IP, gain/loss-of-function, ERK analysis, xenograft","pmids":["38743987"],"confidence":"Medium","gaps":["Ubiquitination site(s) on ABI1 not defined"]},{"year":2026,"claim":"Resolved a spectrin-tethered reservoir mechanism whereby pathogen-induced calpain cleavage releases cortical ABI1 to bind EPS8 and activate its actin-capping activity for protrusion-based cell-to-cell spread.","evidence":"Conditional KO mouse, Co-IP, calpain inhibition, Ca2+ imaging, protrusion/spread assay during Listeria infection","pmids":["41974702"],"confidence":"High","gaps":["Generality of spectrin-tethered ABI1 pool beyond infection unknown"]},{"year":null,"claim":"How ABI1's many phosphorylation sites, splice isoforms, and competing proteolysis routes are integrated to select between WAVE-driven protrusion, N-WASP-driven trafficking, nuclear transcription, and kinase regulation in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length ABI1 in its complexes","Quantitative rules governing isoform/PTM-dependent partner choice undefined","In vivo coordination of cytoplasmic vs nuclear ABI1 pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,5,6,20,22,33]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,7,8,39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,23,30,47]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,17,39]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,8,39,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,8,39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,15,30]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,13,14,47]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,28,37,44]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,20,35,36,50]}],"complexes":["WAVE regulatory complex (WAVE2-ABI1-NAP1-PIR121)","EPS8-ABI1-SOS1 tri-complex"],"partners":["WAVE2","EPS8","SOS1","ABL1","WASL","PIK3R1","ITGA4","SHANK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZP0","full_name":"Abl interactor 1","aliases":["Abelson interactor 1","Abi-1","Abl-binding protein 4","AblBP4","Eps8 SH3 domain-binding protein","Eps8-binding protein","Nap1-binding protein","Nap1BP","Spectrin SH3 domain-binding protein 1","e3B1"],"length_aa":508,"mass_kda":55.1,"function":"May act in negative regulation of cell growth and transformation by interacting with nonreceptor tyrosine kinases ABL1 and/or ABL2. May play a role in regulation of EGF-induced Erk pathway activation. Involved in cytoskeletal reorganization and EGFR signaling. Together with EPS8 participates in transduction of signals from Ras to Rac. In vitro, a trimeric complex of ABI1, EPS8 and SOS1 exhibits Rac specific guanine nucleotide exchange factor (GEF) activity and ABI1 seems to act as an adapter in the complex. Regulates ABL1/c-Abl-mediated phosphorylation of ENAH. Recruits WASF1 to lamellipodia and there seems to regulate WASF1 protein level. In brain, seems to regulate the dendritic outgrowth and branching as well as to determine the shape and number of synaptic contacts of developing neurons","subcellular_location":"Cytoplasm; Nucleus; Cell projection, lamellipodium; Cell projection, filopodium; Cell projection, growth cone; Postsynaptic density; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q8IZP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABI1","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCKAP1","stoichiometry":10.0},{"gene":"SLC1A3","stoichiometry":4.0},{"gene":"WASF2","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"BAIAP2","stoichiometry":0.2},{"gene":"CSNK1G3","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"PFN1","stoichiometry":0.2},{"gene":"WASF1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ABI1","total_profiled":1310},"omim":[{"mim_id":"614989","title":"EPS8-LIKE PROTEIN 3; EPS8L3","url":"https://www.omim.org/entry/614989"},{"mim_id":"614988","title":"EPS8-LIKE PROTEIN 2; EPS8L2","url":"https://www.omim.org/entry/614988"},{"mim_id":"614987","title":"EPS8-LIKE PROTEIN 1; EPS8L1","url":"https://www.omim.org/entry/614987"},{"mim_id":"609061","title":"ENAH ACTIN REGULATOR; ENAH","url":"https://www.omim.org/entry/609061"},{"mim_id":"606442","title":"ABL INTERACTOR 2; ABI2","url":"https://www.omim.org/entry/606442"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABI1"},"hgnc":{"alias_symbol":["E3B1","ABI-1"],"prev_symbol":["SSH3BP1"]},"alphafold":{"accession":"Q8IZP0","domains":[{"cath_id":"2.30.30.40","chopping":"448-501","consensus_level":"high","plddt":93.785,"start":448,"end":501},{"cath_id":"1.20.58","chopping":"1-113","consensus_level":"medium","plddt":96.9555,"start":1,"end":113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZP0-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABI1","jax_strain_url":"https://www.jax.org/strain/search?query=ABI1"},"sequence":{"accession":"Q8IZP0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZP0"}},"corpus_meta":[{"pmid":"11208021","id":"PMC_11208021","title":"The ABI1 and ABI2 protein phosphatases 2C act in a negative feedback regulatory loop of the abscisic acid signalling pathway.","date":"2001","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11208021","citation_count":449,"is_preprint":false},{"pmid":"10521520","id":"PMC_10521520","title":"ABI1 protein phosphatase 2C is a negative regulator of abscisic acid signaling.","date":"1999","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/10521520","citation_count":432,"is_preprint":false},{"pmid":"11701885","id":"PMC_11701885","title":"Abscisic acid activation of plasma membrane Ca(2+) channels in guard cells requires cytosolic NAD(P)H and is differentially disrupted upstream and downstream of reactive oxygen species production in abi1-1 and abi2-1 protein phosphatase 2C mutants.","date":"2001","source":"The Plant 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From synaptic plasticity to tumor cell migration].","date":"2013","source":"Der Pathologe","url":"https://pubmed.ncbi.nlm.nih.gov/24196611","citation_count":4,"is_preprint":false},{"pmid":"16025998","id":"PMC_16025998","title":"[The role of EGF receptor-dependent e3B1/Abi1 protein as a tumor suppressor protein in malignant tumors].","date":"2005","source":"Orvosi hetilap","url":"https://pubmed.ncbi.nlm.nih.gov/16025998","citation_count":3,"is_preprint":false},{"pmid":"15178460","id":"PMC_15178460","title":"Pak regulates calpain-dependent degradation of E3b1.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15178460","citation_count":3,"is_preprint":false},{"pmid":"23558677","id":"PMC_23558677","title":"Abelson interactor 1 (ABI1) and its interaction with Wiskott-Aldrich syndrome protein (wasp) are critical for proper eye formation in Xenopus embryos.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23558677","citation_count":3,"is_preprint":false},{"pmid":"40811817","id":"PMC_40811817","title":"Ethylene antagonizes ABA responses in stomatal movement and seed germination by upregulating ABI1 and ABI2 at both the transcript and protein levels.","date":"2025","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40811817","citation_count":2,"is_preprint":false},{"pmid":"38626565","id":"PMC_38626565","title":"Circulating miR-30e-3p induces disruption of neurite development in SH-SY5Y cells by targeting ABI1, a novel biomarker for schizophrenia.","date":"2024","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/38626565","citation_count":2,"is_preprint":false},{"pmid":"39568082","id":"PMC_39568082","title":"Programmed cell death-related ABI1 is a critical mediator of abdominal aortic aneurysm.","date":"2024","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/39568082","citation_count":0,"is_preprint":false},{"pmid":"41974702","id":"PMC_41974702","title":"A pore-forming toxin initiates ABI1 complex switching to promote bacterial cell-to-cell spread.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41974702","citation_count":0,"is_preprint":false},{"pmid":"41618774","id":"PMC_41618774","title":"AlphaFold2 Insights into c-Abl Transactivation by Adaptor c-Crk or Abi-1: Structural Forms, Active Site Types, and Multiple SH3-PxxPxK/R Interactions.","date":"2026","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/41618774","citation_count":0,"is_preprint":false},{"pmid":"38743987","id":"PMC_38743987","title":"CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38743987","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50509,"output_tokens":11930,"usd":0.165239,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22865,"output_tokens":7806,"usd":0.154738,"stage2_stop_reason":"end_turn"},"total_usd":0.319977,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"E3B1/ABI1 was identified as a binding partner of the EPS8 SH3 domain and the ABL SH3 domain in vitro, and associates with EPS8 in vivo; the protein exists as multiple phosphoserine-containing isoforms (65, 68, 72 kDa) whose hyperphosphorylation is induced by EGF stimulation.\",\n      \"method\": \"SH3-domain library screen, in vitro binding assay, in vivo co-immunoprecipitation, phosphatase digestion and phosphoamino acid analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding, single lab, two orthogonal methods\",\n      \"pmids\": [\"9010225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EPS8 and E3B1/ABI1 transduce signals from Ras to Rac by forming a tri-complex with SOS-1 that exhibits Rac-specific GEF activity in vitro, placing ABI1 as an essential scaffold in the Ras→Rac signaling axis.\",\n      \"method\": \"In vivo co-immunoprecipitation, in vitro Rac-GEF activity assay, epistatic signaling analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of GEF activity with defined complex, replicated across multiple methods and independently followed up\",\n      \"pmids\": [\"10499589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ABI1 (human ABI-1) was identified as a fusion partner of MLL in acute myeloid leukemia with t(10;11)(p11.2;q23); the MLL-ABI1 fusion combines MLL AT-hook/DNA methyltransferase homology domains with ABI1's homeodomain homology region, polyproline stretches, and SH3 domain.\",\n      \"method\": \"RT-PCR cloning of chimeric transcripts, chromosomal localization, sequence analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural identification of fusion transcript confirmed in two independent cases\",\n      \"pmids\": [\"9694699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Abi-1 and Abi-2 proteins are expressed in the developing nervous system, are concentrated in synaptosomes and growth cone particles, and their phosphorylation state changes with age in brain lysates, consistent with participation in Abl kinase signaling at neuronal structures.\",\n      \"method\": \"Subcellular fractionation, immunohistochemistry, Western blotting of brain lysates\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by fractionation and IHC, single lab, no direct functional consequence tested\",\n      \"pmids\": [\"10995551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ABI-1 SH3 domain interacts with ENL (an MLL fusion partner) via an internal ENL region; the interaction was confirmed by yeast two-hybrid, far-Western blot, GST pulldown, and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, far-Western blot, GST pulldown, co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding methods, single lab\",\n      \"pmids\": [\"10777208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PI3K (via its p85 regulatory subunit) is recruited by ABI1 into the EPS8-ABI1-SOS1 complex; PIP3 (the PI3K catalytic product) and p85 recruitment cooperate to unmask the Rac-GEF activity of the complex in vitro and are required for Rac activation and actin remodeling in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro Rac-GEF assay, dominant-negative and KO cell experiments, colocalization studies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GEF reconstitution combined with cell-based loss-of-function, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12515821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ABI1 directly interacts with the WHD domain of WAVE2, stimulates WAVE2-mediated actin polymerization activity in vitro, and mediates assembly of the WAVE2-ABI1-NAP1-PIR121 complex; RNAi knockdown of ABI1 abrogates Rac-dependent lamellipodia protrusion in vivo.\",\n      \"method\": \"Tandem mass spectrometry, in vitro actin polymerization assay, co-immunoprecipitation, RNAi knockdown with live-cell imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of actin nucleation activity, RNAi phenotypic rescue, MS identification, multiple orthogonal methods\",\n      \"pmids\": [\"15048123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ABI1 binds WAVE1 through an amino-terminal WAVE-binding (WAB) domain; disruption of this interaction prevents ABI1 from reaching lamellipodia tips and reduces WAVE1 protein levels in fibroblasts lacking one Abi1 allele and null for Abi2, an effect rescued by Abi1 constructs retaining WAVE1 binding. ABI1 also contains an overlapping SNARE domain that interacts with Syntaxin-1 and undergoes leptomycin B-sensitive nucleocytoplasmic shuttling.\",\n      \"method\": \"Domain mapping, rescue experiments in MEFs, co-immunoprecipitation, leptomycin B treatment, live-cell localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with functional rescue, multiple cell-based methods, single lab\",\n      \"pmids\": [\"15143189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ABI1 binds N-WASP with nanomolar affinity and, cooperating with Cdc42, potently induces N-WASP actin polymerization activity in vitro. ABI1 and WAVE are both required for Rac-dependent membrane protrusion and macropinocytosis, whereas ABI1 and N-WASP (but not WAVE) regulate actin-based vesicular transport, EGFR endocytosis, and receptor surface distribution.\",\n      \"method\": \"In vitro actin polymerization assay, binding affinity measurements, RNAi knockdown, EGFR endocytosis assay, macropinocytosis assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with affinity measurement, RNAi loss-of-function with multiple distinct phenotypic readouts, single study with orthogonal methods\",\n      \"pmids\": [\"16155590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Eps8 promotes actin filopodia-like structures; interaction with ABI1 modulates actin architecture toward cables and star-like structures, and the Eps8/ABI1 complex recruits N-WASP to regulate actin nucleator localization/activity.\",\n      \"method\": \"Overexpression in cultured cells and Xenopus embryos, colocalization, dominant-negative constructs\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression assays without reconstitution or clean loss-of-function rescue\",\n      \"pmids\": [\"16225669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In response to CSF-1, WAVE2 and ABI1 form a stable complex in macrophages and are co-recruited to F-actin-rich protrusions; knockdown of either WAVE2 or ABI1 by RNAi impairs CSF-1-induced membrane protrusions and macrophage migration.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, dominant-negative constructs, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with RNAi phenotype, single lab, two methods\",\n      \"pmids\": [\"16280551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ABI1 interacts with betaPIX (a Rac1 GEF) via its C-terminal region in vitro and via N-terminal region in vivo; co-expression of ABI1 with truncated betaPIX blocks PDGF-induced dorsal membrane ruffle formation.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown, co-immunoprecipitation, overexpression functional assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding assays with limited functional follow-up\",\n      \"pmids\": [\"16940963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ABI1 is localized in neurites, growth cones, and later enriched in dendritic spines and PSDs. It co-immunoprecipitates with the ProSAP2/Shank3 scaffold and with Eps8/SOS1. Upon NMDA stimulation, ABI1 translocates from PSDs to nuclei in an Abl kinase-dependent manner, where it associates with Myc/Max transcription factor complex and enhances E-box-regulated gene transcription. Knockdown causes excessive dendritic branching and immature spine/synapse morphology.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, nuclear translocation assay, reporter gene assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RNAi phenotype, reporter assay, live imaging), single lab\",\n      \"pmids\": [\"17304222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Chlamydia trachomatis infection promotes Rac interaction with WAVE2 and ABI1 (but not IRSp53) as shown by co-immunoprecipitation; siRNA depletion of WAVE2 or ABI1 abrogates chlamydia-induced actin recruitment and significantly reduces uptake.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, infection assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss-of-function RNAi with defined phenotypic readout, single lab\",\n      \"pmids\": [\"17501982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Abi-1 forms an EGF-inducible complex with the Cbl ubiquitin ligase; an Abi-1 mutant lacking the SH3 domain fails to interact with Cbl, inhibits EGFR internalization, and prevents Cbl membrane accumulation after EGF. Oncogenic Abl disrupts the EGF-inducible Abi-1/Cbl complex.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, EGFR internalization assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain-mapping and functional internalization assay, single lab\",\n      \"pmids\": [\"17395426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Phosphotyrosine pY213 of ABI1 allosterically inhibits nonmyristoylated c-Abl kinase in trans by concurrent binding of pY213 to the Abl SH2 domain and a proximal PXXP motif to the Abl SH3 domain; wild-type ABI1 (but not Y213F mutant) inhibits Abl pY412 autophosphorylation in vivo.\",\n      \"method\": \"In vitro kinase assay with phosphopeptides, mutagenesis (Y213F), co-expression in cells, phosphorylation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical mechanism with mutagenesis, validated in cells with orthogonal methods\",\n      \"pmids\": [\"18328268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In C. elegans, ABI-1 interacts with the UNC-53/NAV2 scaffolding protein via a restricted calponin homology (CH) domain of UNC-53; ABI-1 and UNC-53 share overlapping expression and similar cell-migration phenotypes, and ABI-1 links UNC-53 to the ARP2/3 complex for actin remodeling during cell migration.\",\n      \"method\": \"Yeast two-hybrid, domain mapping, phenotypic analysis of mutants, RNAi of actin-regulatory partners\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus physical interaction mapping, ortholog validated in C. elegans\",\n      \"pmids\": [\"19168673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ABI1 isoform 3 (lacking exon 10) constitutively activates Rac1 and promotes macropinocytosis; isoform 2 (containing exon 10) preferentially binds activated Rac1 via an exon-10 site, suppresses macropinocytosis, and is more cytoplasmic. Both isoforms bind inactive Rac1 through a non-exon-10 site.\",\n      \"method\": \"Flow cytometry macropinocytosis assay, Rac1 activation assay, in vitro binding with exon-10 domain, subcellular fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (flow cytometry, in vitro binding, fractionation), single lab\",\n      \"pmids\": [\"20479892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ABI1 pY213 links Abl kinase signaling to the p85 regulatory subunit of PI3K: phosphorylation of Y213 is required for Abl to regulate macropinocytosis, and pY213 interacts with the C-terminal SH2 domain of p85.\",\n      \"method\": \"SH2 domain library screen, interaction mapping, loss-of-function Y213 mutant, macropinocytosis assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain library screen plus mutagenesis and functional assay, single lab\",\n      \"pmids\": [\"20598684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dysbindin-1 interacts with WAVE2 (but not N-WASP) and with ABI1, and dysbindin-1 promotes the WAVE2-ABI1 interaction; the three proteins form a ternary complex. RNAi knockdown of dysbindin-1 produces abnormally elongated immature dendritic protrusions, phenocopying ABI1 loss.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying ternary complex and RNAi phenotype, single lab\",\n      \"pmids\": [\"20531346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Integrity of the SOS1/EPS8/ABI1 tri-complex is essential for LPA-induced Rac activation, cell migration, and peritoneal metastatic colonization of ovarian cancer cells; ABI1 acts as the scaffold holding SOS1 and EPS8 together in the complex.\",\n      \"method\": \"Co-immunoprecipitation, knockdown, re-expression rescue, in vivo metastasis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with loss-of-function and gain-of-function rescue, in vivo confirmation, single lab\",\n      \"pmids\": [\"21118970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Abi1 directly binds the α4 integrin cytoplasmic tail (confirmed by purified protein binding assay), colocalizes with phosphorylated α4 at the leading edge, and Abi1-deficient cells expressing α4 have impaired cell spreading rescued by wild-type but not α4-binding-deficient Abi1.\",\n      \"method\": \"Direct binding assay with purified proteins, co-localization, KO mouse, rescue with Abi1 mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding with purified proteins plus KO mouse with mutant rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21173240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Abi1 knockout in mice causes embryonic lethality (~E11.5) with heart and brain malformations. Abi1-KO cells show reduced WAVE1, WAVE2, NAP1, and Sra-1/PIR121 levels, decreased migration rate and distance, and decreased dorsal ruffling, demonstrating that Abi1 is critical for WAVE complex integrity and stability.\",\n      \"method\": \"Conditional KO mouse, Western blotting, cell migration assay, ruffling assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal readouts, replicated across cell and organismal levels\",\n      \"pmids\": [\"21482783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CDK1/cyclin B phosphorylates ABI1 at serine 216 at mitotic entry, and this phosphorylation attenuates Bcr-Abl-induced tyrosine phosphorylation of the WAVE complex and F-actin assembly; phosphomimetic S216D mutation in ABI1 is sufficient to recapitulate this attenuation and interferes with cell cycle progression.\",\n      \"method\": \"In vitro kinase assay, phosphomimetic mutagenesis, cell cycle analysis, F-actin assembly assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay combined with phosphomimetic mutation and functional cell-cycle/actin readouts\",\n      \"pmids\": [\"21900237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Abi1 knockdown by shRNA in Bcr-Abl-transformed cells attenuates abnormal actin remodeling, inhibits cell adhesion and migration on fibronectin, and impairs leukemogenesis in NOD/SCID mice; Abi1 silencing also attenuates Bcr-Abl-stimulated activation of Lyn (Src family kinase).\",\n      \"method\": \"shRNA knockdown, actin remodeling assay, adhesion/migration assay, in vivo leukemogenesis assay, kinase activity assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts including in vivo, single lab\",\n      \"pmids\": [\"18453543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Abi-1 and CaMKIIα interact at resting conditions through Abi1's tSNARE domain (which has homology to CaMKIIα regulatory domain); this interaction mutually inhibits both proteins including Abi1-dependent Rac activation. Glutamate receptor activation causes calmodulin binding leading to dissociation; CaMKIIα phosphorylates Abi1 at serine 88 prior to dissociation, contributing to Rac activation and spine maturation.\",\n      \"method\": \"Co-immunoprecipitation, FRET-based activity sensors, mutagenesis, spine morphology analysis in neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with FRET-based activity measurement and mutagenesis, single lab\",\n      \"pmids\": [\"22993434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"An SK3 channel/nWASP/Abi-1 trimeric complex is present in neural stem cells and postsynaptic compartments; SK3 and nWASP act synergistically to induce filopodial outgrowth, while Abi-1 acts antagonistically to these partners to regulate neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, pharmacological SK3 channel activation, fluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and overexpression only, single lab, no clean loss-of-function rescue\",\n      \"pmids\": [\"21464958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPK interacts with the Abi-1 SH3 domain through the hnRNPK KI domain; knockdown of hnRNPK phenocopies Abi-1 knockdown (enlarged dendritic tree, increased filopodia, decreased mature synapses), indicating synergistic function in a multiprotein complex regulating spine/filopodia balance.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, fluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with knockdown phenotype, single lab, no reconstitution\",\n      \"pmids\": [\"22102872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C. elegans ABI-1 SH3 domain directly binds MIG-10 (lamellipodin); epistasis analysis places ABI-1 and WVE-1 downstream of MIG-10 to mediate axon guidance in both UNC-6 (netrin) and SLT-1 (slit) pathways; this ABI-1/MIG-10 interaction also promotes lamellipodia formation in cultured mammalian cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, domain mapping, epistasis analysis, cell-based lamellipodia assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus physical interaction with cross-species validation, single lab\",\n      \"pmids\": [\"23209429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MIG-10B isoform interacts with ABI-1 to organize the actin cytoskeleton at presynaptic sites and instruct synaptic vesicle clustering through Synapsin-1 (SNN-1) downstream of Netrin; a dominant-negative MIG-10B construct expressing a specific N-terminal domain disrupts vesicle clustering and thermotaxis behavior in vivo.\",\n      \"method\": \"Genetic analysis, domain mapping, dominant-negative construct, in vivo behavioral assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with dominant-negative construct, single lab\",\n      \"pmids\": [\"23028145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Stimulation with acetylcholine induces Abi1 association with N-WASP in smooth muscle; Abi1 knockdown inhibits N-WASP activation, actin polymerization, and contraction without affecting myosin light chain phosphorylation. A multiprotein complex of c-Abl, CAS, and Abi1 forms upon contractile activation, and Abi1 is activated by c-Abl/CAS while Abi1 reciprocally controls c-Abl activation (pY412) and CAS interaction.\",\n      \"method\": \"Co-immunoprecipitation, lentiviral RNAi, FRET-based N-WASP sensor, actin polymerization assay, contraction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — FRET sensor for activity, reconstitution of multi-protein complex, RNAi with multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"23740246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Y435-phosphorylated ABI1 localizes at sites of extracellular matrix degradation in colorectal carcinoma cells; RNAi knockdown of ABI1 suppresses matrix dissolution by 95%, and STI571 treatment abolishes ABI1 Y435-phosphorylation and suppresses matrix degradation, fibronectin attachment, and cell invasion.\",\n      \"method\": \"RNAi knockdown, matrix degradation assay, STI571 kinase inhibitor treatment, immunofluorescence\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function and pharmacological inhibition with quantitative functional assays, single lab\",\n      \"pmids\": [\"24913355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Activated Rac1 specifically binds to a site encoded by exon 10 in ABI1 isoform 2 in vitro; because exon 10 is absent in isoform 3 due to alternative splicing, the isoform-2 WAVE2 complex and isoform-3 WAVE2 complex display differential binding to activated versus inactive Rac1.\",\n      \"method\": \"In vitro binding assay with activated/inactive Rac1, domain mapping by exon exclusion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with domain evidence, single lab\",\n      \"pmids\": [\"20479892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ABI1 acts as a scaffold protein in the SOS1/EPS8/ABI1 tri-complex: the SH3 domain of ABI1 mediates SOS1 binding, and the poly-proline+PxxDY region mediates EPS8 binding; TAT-conjugated inhibitory peptides disrupting ABI1-EPS8 interaction suppress ovarian cancer invasion and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, domain deletion mapping, in vivo peritoneal metastasis assay with inhibitory peptides\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping plus in vivo functional validation with peptide inhibitors, single lab\",\n      \"pmids\": [\"31488087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ABI1 bridges c-Abl and WAVE2: a linker region between the proline-rich and SH3 domains of ABI1 is required for c-Abl interaction and c-Abl-mediated WAVE2 phosphorylation; the NESH/Abi-3-based WAVE2 complex, lacking this c-Abl-binding linker, is unable to generate lamellipodial protrusions and instead may promote invadopodia.\",\n      \"method\": \"Domain deletion analysis, co-immunoprecipitation, imatinib/siRNA knockdown, morphological assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with functional phenotypic readouts, single lab\",\n      \"pmids\": [\"26428302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Bone marrow-specific deletion of Abi1 in mice results in an MPN-like phenotype with increased activity of Src family kinases (SFKs), STAT3, and NF-κB signaling, impaired hematopoietic stem cell self-renewal, and features resembling human myelofibrosis; ABI1 thus negatively regulates SFK/STAT3/NF-κB signaling in hematopoietic cells.\",\n      \"method\": \"Conditional KO mouse, bone marrow transplantation, kinase activity assays, signaling pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with competitive transplantation, multiple signaling pathway readouts, corroborated in patient samples\",\n      \"pmids\": [\"30213875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ABI1 loss in benign prostate epithelial cells induces EMT and activation of non-canonical WNT signaling; FYN SH2 domain interacts with ABI1 pY421 (high-affinity), and ABI1 loss leads to increased STAT3 phosphorylation downstream of FZD2, suggesting ABI1 inhibits EMT through suppressing FYN-STAT3 activation.\",\n      \"method\": \"CRISPR/Cas9 gene disruption, RNA sequencing, Western blotting, SH2-ABI1 interaction assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with RNA-seq pathway analysis and protein interaction, single lab\",\n      \"pmids\": [\"31530281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTEN dephosphorylates ABI1 at Y213 and S216 (identified by phosphotyrosine immunoprecipitation/MS), leading to ABI1 degradation through the calpain pathway; this down-regulates the WAVE regulatory complex, reorganizes the actin cytoskeleton, and is required for epiblast epithelial polarization.\",\n      \"method\": \"Phosphotyrosine IP/mass spectrometry, PTEN mutant reconstitution in embryoid bodies, calpain inhibitor rescue, embryoid body polarization assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MS-based substrate identification, PTEN mutant reconstitution, pathway rescue with calpain inhibitor, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32673396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTEN's protein phosphatase activity dephosphorylates and downregulates ABI1 in breast cancer cells; gain- and loss-of-function of ABI1 demonstrates that ABI1 mediates PTEN-loss-induced EMT and cancer stem cell activity.\",\n      \"method\": \"PTEN reconstitution (WT vs. mutant), gain/loss-of-function of ABI1, EMT marker analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTEN mutant analysis with ABI1 gain/loss-of-function rescue, single lab\",\n      \"pmids\": [\"32728066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ABI1 localizes to the tip of lamellipodia and its protrusion coordinates with F-actin at the leading edge; ABI1 knockdown reduces smooth muscle cell migration and decreases leading-edge recruitment of profilin-1 (Pfn-1, identified as a new ABI1 partner), c-Abl, and N-WASP but not pVASP, cortactin, or vinculin. Integrin β1 and c-Abl regulate ABI1 positioning at the leading edge.\",\n      \"method\": \"shRNA knockdown/rescue, live-cell imaging, co-immunoprecipitation, leading-edge protein localization assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with multiple protein localization readouts and Co-IP for new binding partner, single lab\",\n      \"pmids\": [\"32606387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Y398 in the SH3 domain of Abi-1 is a new phosphorylation site; combined disruption of Y213 and Y398 significantly weakens Abi-1 binding to c-Abl (SH3-Abl proline-rich domain interaction); Abi-1 phosphorylation at both sites stimulates Mena phosphorylation through c-Abl kinase activation.\",\n      \"method\": \"Mutagenesis, in vitro kinase assay, binding assay, phosphorylation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, single lab, limited replication\",\n      \"pmids\": [\"21320496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"E3B1/ABI1 levels are regulated by the Ca2+-activated protease calpain; serum starvation activates calpain-dependent E3B1 degradation, which is prevented by constitutively active PAK1 or by Rac1 activation downstream of PDGF; conversely, PAK auto-inhibitory domain expression causes E3B1 degradation even in serum.\",\n      \"method\": \"Calpain inhibitor treatment, constitutively active/dominant-negative constructs, Western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological and overexpression approaches, single lab, no direct reconstitution\",\n      \"pmids\": [\"15178460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Abi1 mediates airway smooth muscle (ASM) cell proliferation by regulating JAK2 and STAT3 activation; Abi1 knockdown reduces JAK2 and STAT3 activation and ASM proliferation.\",\n      \"method\": \"shRNA loss-of-function, kinase/STAT3 phosphorylation assay, proliferation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with kinase/transcription factor readout and proliferation assay, single lab\",\n      \"pmids\": [\"35198891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9 knockout of Abi1 in Bcr-Abl-transformed hematopoietic cells reduces ERK and PI3K/Akt signaling, inhibits IL3-independent growth and SDF-1α-mediated chemotaxis, abrogates abnormal actin remodeling, and abolishes leukemogenesis in syngeneic mice.\",\n      \"method\": \"CRISPR/Cas9 KO, signaling pathway analysis, in vivo leukemogenesis assay\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple signaling readouts and in vivo confirmation, single lab\",\n      \"pmids\": [\"32276588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Xenopus Abi1 knockdown by morpholino disrupts eye morphogenesis; the SH3 domain of Abi1 is required for proper retinal progenitor cell movement and differentiation, and this requires an interaction with WASP (Wiskott-Aldrich syndrome protein).\",\n      \"method\": \"Morpholino knockdown, SH3 domain rescue constructs, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with domain-specific rescue, in vivo Xenopus model\",\n      \"pmids\": [\"23558677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of MBNL1 promotes expression of the Abi1-Δe10 splice isoform (lacking exon 10); Abi1-Δe10 activates Rac1 independently of upstream stimulation and triggers the Rac1-NOX1-ROS pathway leading to KLF4 upregulation, VSMC macrophage-like transdifferentiation, increased proliferation and migration.\",\n      \"method\": \"MBNL1 knockdown, splice isoform expression analysis, Rac1 activation assay, NOX1-ROS pathway analysis, VSMC phenotyping\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splice isoform-specific functional assays with pathway analysis, single lab\",\n      \"pmids\": [\"33759281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Caskin2 associates with the WAVE regulatory complex in an ABI1-dependent manner to promote cell migration; growth factor-induced phosphorylation of Caskin2 at serine 878 regulates the Caskin2-ABI1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, phospho-mutant analysis, cell migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with phosphomutant, single lab, limited mechanistic depth for ABI1 specifically\",\n      \"pmids\": [\"38587458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"During Listeria monocytogenes infection, the pore-forming toxin LLO triggers Ca2+ influx leading to calpain-mediated spectrin cleavage; this mobilizes ABI1 from its spectrin-bound cortical state, allowing ABI1 to bind EPS8 within protrusions and activate EPS8's actin-capping activity to enable actin recycling and protrusion elongation for cell-to-cell spread. Conditional Abi1 KO mice show significantly reduced Lm infection susceptibility.\",\n      \"method\": \"Conditional KO mouse, co-immunoprecipitation, calpain inhibitor assay, Ca2+ imaging, protrusion/spread assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with multiple biochemical and cell biological readouts defining molecular mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"41974702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABI1 is imported to the plant cell nucleus by SAD2 (an importin β family protein) upon coronatine (COR) treatment; nuclear ABI1 accumulation requires SAD2 and enables COR to antagonize ABA signaling and reopen stomata during bacterial pathogen invasion.\",\n      \"method\": \"Subcellular localization assay, sad2 mutant analysis, COR treatment, stomatal aperture assay\",\n      \"journal\": \"The Plant journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization assay tied to functional stomatal phenotype in sad2 mutant, single lab\",\n      \"pmids\": [\"38683723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CaMKIIα phosphorylates Shank3 at Ser685; this phosphorylation significantly increases binding of ABI1 to Shank3 in vitro (pre-phosphorylated GST-Shank3), whereas Ser685Ala or Ser685Asp mutation reduces ABI1-Shank3 co-immunoprecipitation from cells.\",\n      \"method\": \"In vitro kinase assay with purified CaMKIIα, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation assay with mutagenesis, single lab\",\n      \"pmids\": [\"31983435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ABI1 degradation through ubiquitination by the E3 ligase CBLC activates ERK signaling in colorectal cancer; ABI1 upregulation abolishes the pro-tumorigenic effects of CBLC.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, gain/loss-of-function, ERK pathway analysis, xenograft assay\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay combined with gain/loss-of-function rescue and in vivo model, single lab\",\n      \"pmids\": [\"38743987\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABI1 (Abelson interactor 1/E3B1) functions as a multivalent scaffold protein that (i) nucleates and maintains the WAVE regulatory complex (directly binding WAVE1/2 WHD domain) to stimulate Arp2/3-dependent actin polymerization at lamellipodia and other protrusive structures; (ii) assembles an EPS8-ABI1-SOS1 tri-complex with Rac-specific GEF activity downstream of Ras and PI3K/p85; (iii) allosterically regulates c-Abl kinase through phospho-Y213 and pY398 binding in trans to its SH2 and SH3 domains; (iv) is post-translationally regulated by CDK1 (S216 phosphorylation at mitosis), CaMKIIα (S88 phosphorylation), PTEN (Y213/S216 dephosphorylation leading to calpain-dependent degradation), and CBLC ubiquitin ligase; (v) undergoes nucleocytoplasmic shuttling and, upon synaptic stimulation, translocates to the nucleus to co-activate Myc/Max-dependent transcription; and (vi) controls smooth muscle and hematopoietic cell signaling via JAK2/STAT3 and SFK/NF-κB pathways, with loss of ABI1 causing myeloproliferative disease, EMT, and impaired epithelial morphogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABI1 (Abelson interactor 1/E3B1) is a multivalent cytoskeletal scaffold that couples Rho-family GTPase and tyrosine-kinase signaling to Arp2/3-dependent actin polymerization at protrusive structures [#1, #6]. Its central function is to nucleate and stabilize the WAVE regulatory complex: ABI1 binds the WHD domain of WAVE2 and an N-terminal WAVE-binding domain of WAVE1 to stimulate WAVE-mediated actin polymerization and assemble the WAVE2-NAP1-PIR121 complex, and Abi1 loss in mice destabilizes WAVE1/WAVE2/NAP1/Sra-1, abolishes lamellipodial protrusion, and causes embryonic lethality with heart and brain malformations [#6, #7, #22]. In parallel, ABI1 acts as the scaffold of an EPS8-ABI1-SOS1 tri-complex (SH3 domain binding SOS1, proline-rich/PxxDY region binding EPS8) that, upon recruitment of the PI3K p85 subunit and PIP3, exhibits Rac-specific GEF activity downstream of Ras to drive actin remodeling [#1, #5, #33]. ABI1 also directly activates N-WASP cooperatively with Cdc42 to govern actin-based vesicular transport, EGFR endocytosis, and macropinocytosis, functions distinct from its WAVE-dependent membrane protrusion role [#8]. ABI1 allosterically regulates c-Abl: phospho-Y213 binds the Abl SH2 domain in trans while a proximal PXXP motif engages the Abl SH3 domain, and ABI1 reciprocally bridges c-Abl to WAVE2 phosphorylation [#15, #34]. Its activity is gated by post-translational control including CDK1/cyclin B phosphorylation at S216 at mitosis, CaMKII\\u03b1 phosphorylation at S88, and PTEN-mediated Y213/S216 dephosphorylation that triggers calpain-dependent degradation and reorganizes the actin cytoskeleton during epithelial polarization [#23, #25, #37]. Alternative splicing of exon 10 produces isoforms with opposite Rac1-binding and macropinocytosis behavior [#17, #32]. Beyond actin, synaptically stimulated ABI1 translocates to the nucleus in an Abl-dependent manner to co-activate Myc/Max E-box transcription and shapes dendritic spine and synapse maturation [#12]. Loss of ABI1 in hematopoietic cells causes a myeloproliferative/myelofibrosis-like disease through derepressed SFK/STAT3/NF-\\u03baB signaling, and ABI1 loss promotes EMT, while ABI1 is a fusion partner of MLL in acute myeloid leukemia [#2, #35, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established ABI1 as a phosphoprotein adaptor by showing it binds the SH3 domains of EPS8 and ABL and is hyperphosphorylated on serine after EGF stimulation, framing it as a receptor-coupled scaffold.\",\n      \"evidence\": \"SH3-domain library screen, in vitro binding and reciprocal Co-IP, phosphoamino acid analysis\",\n      \"pmids\": [\"9010225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of EPS8/ABL binding not yet defined\", \"Kinase driving serine hyperphosphorylation unidentified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified ABI1 as an MLL fusion partner in t(10;11) AML, linking the scaffold to leukemogenesis at the structural level.\",\n      \"evidence\": \"RT-PCR cloning of chimeric MLL-ABI1 transcripts and chromosomal mapping in patient cases\",\n      \"pmids\": [\"9694699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oncogenic mechanism of the fusion protein not tested\", \"Contribution of ABI1 moiety vs MLL moiety unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed ABI1 scaffolds an EPS8-SOS1 tri-complex with Rac-specific GEF activity, placing ABI1 mechanistically in the Ras\\u2192Rac signaling axis.\",\n      \"evidence\": \"In vivo Co-IP, in vitro Rac-GEF activity assay, epistatic signaling analysis\",\n      \"pmids\": [\"10499589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GEF activity is switched on in cells not yet defined\", \"Structural basis of complex assembly unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the activation input for the tri-complex by showing PI3K p85 recruitment and PIP3 unmask its Rac-GEF activity, connecting lipid signaling to actin remodeling.\",\n      \"evidence\": \"Co-IP, in vitro Rac-GEF assay, dominant-negative and KO cell experiments\",\n      \"pmids\": [\"12515821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative stoichiometry of activation not measured\", \"Spatial control of p85 recruitment unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established ABI1 as a core WAVE-complex subunit by mapping direct WHD/WAB-domain binding to WAVE2/WAVE1, demonstrating it stimulates actin polymerization and is needed for lamellipodia.\",\n      \"evidence\": \"Mass spectrometry, in vitro actin polymerization assay, RNAi knockdown with live imaging, domain-mapping rescue in MEFs\",\n      \"pmids\": [\"15048123\", \"15143189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo organismal requirement not yet tested at this stage\", \"SNARE-domain/Syntaxin-1 functional role undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified calpain-dependent degradation of ABI1 controlled by Rac/PAK as a turnover mechanism, introducing proteolytic regulation of the scaffold.\",\n      \"evidence\": \"Calpain inhibitor treatment and constitutively active/dominant-negative PAK1/Rac1 constructs with Western blotting\",\n      \"pmids\": [\"15178460\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pharmacological/overexpression-only without reconstitution\", \"Direct calpain cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished ABI1's two actin-nucleator arms by showing it directly activates N-WASP with Cdc42 for vesicular transport/EGFR endocytosis, separate from WAVE-driven membrane protrusion.\",\n      \"evidence\": \"In vitro actin polymerization with affinity measurement, RNAi with macropinocytosis and EGFR endocytosis readouts\",\n      \"pmids\": [\"16155590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ABI1 partitions between WAVE and N-WASP pools unknown\", \"Regulation of nucleator choice undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended ABI1's actin role to physiological migration by showing CSF-1-induced WAVE2-ABI1 co-recruitment drives macrophage protrusion and motility.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, dominant-negative constructs, fluorescence microscopy\",\n      \"pmids\": [\"16280551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream receptor-to-complex coupling not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a nuclear/transcriptional function: synaptic NMDA stimulation drives Abl-dependent ABI1 translocation to nuclei where it co-activates Myc/Max, while it shapes dendritic spine maturation.\",\n      \"evidence\": \"Co-IP with Shank3/Eps8/SOS1, siRNA knockdown, nuclear translocation and E-box reporter assays in neurons\",\n      \"pmids\": [\"17304222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-bound complex composition not defined\", \"Target genes activated in vivo unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Tied ABI1 to receptor downregulation by showing an EGF-inducible Abi1-Cbl complex required for EGFR internalization, disrupted by oncogenic Abl.\",\n      \"evidence\": \"Co-IP, SH3-deletion dominant-negative, EGFR internalization assay\",\n      \"pmids\": [\"17395426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Cbl ubiquitinates ABI1 here not tested\", \"Single-lab Co-IP\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the molecular mechanism by which ABI1 allosterically inhibits c-Abl, with pY213 engaging the Abl SH2 domain and a PXXP motif the SH3 domain in trans.\",\n      \"evidence\": \"In vitro kinase assays with phosphopeptides, Y213F mutagenesis, cellular co-expression\",\n      \"pmids\": [\"18328268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular kinase generating pY213 not identified in this study\", \"Reciprocal regulation context-dependence unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected ABI1 tyrosine phosphorylation to lipid signaling, showing pY213 binds the p85 C-terminal SH2 domain and is required for Abl-driven macropinocytosis.\",\n      \"evidence\": \"SH2 domain library screen, Y213 mutant, macropinocytosis assay\",\n      \"pmids\": [\"20598684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical affinity not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed exon-10 alternative splicing functionally diversifies ABI1, with isoform 3 constitutively activating Rac1/macropinocytosis and isoform 2 binding activated Rac1 via the exon-10 site to suppress it.\",\n      \"evidence\": \"Macropinocytosis flow cytometry, Rac1 activation/binding assays, exon-10 domain mapping, fractionation\",\n      \"pmids\": [\"20479892\", \"20479892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific splicing control not defined\", \"Structural basis of differential Rac1 binding unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated the tri-complex is required for cancer cell invasion in vivo, with ABI1 as the obligate scaffold holding SOS1 and EPS8 for LPA-induced Rac activation and ovarian metastasis.\",\n      \"evidence\": \"Co-IP, knockdown/re-expression rescue, in vivo peritoneal metastasis assay\",\n      \"pmids\": [\"21118970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF activity in this metastatic setting not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established ABI1 as essential for organismal development and WAVE-complex stability, with KO causing embryonic lethality and loss of WAVE/NAP1/Sra-1 protein.\",\n      \"evidence\": \"Conditional KO mouse, Western blotting, migration and ruffling assays\",\n      \"pmids\": [\"21482783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-autonomous requirements not dissected\", \"Mechanism stabilizing partner proteins not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Introduced cell-cycle control of ABI1, showing CDK1/cyclin B phosphorylates S216 at mitosis to attenuate Bcr-Abl-driven WAVE phosphorylation and F-actin assembly.\",\n      \"evidence\": \"In vitro kinase assay, S216D phosphomimetic, cell-cycle and F-actin assays\",\n      \"pmids\": [\"21900237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing S216 not identified here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked ABI1 to Bcr-Abl leukemogenesis, showing its knockdown reduces abnormal actin remodeling, adhesion/migration, Lyn activation, and leukemia in vivo.\",\n      \"evidence\": \"shRNA knockdown, actin/adhesion/migration assays, NOD/SCID leukemogenesis, kinase activity assay\",\n      \"pmids\": [\"18453543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role in Lyn activation unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a mutually inhibitory ABI1-CaMKII\\u03b1 interaction via the tSNARE domain and CaMKII\\u03b1-mediated S88 phosphorylation as a calcium-gated switch for Rac activation and spine maturation.\",\n      \"evidence\": \"Co-IP, FRET activity sensors, mutagenesis, neuronal spine morphology\",\n      \"pmids\": [\"22993434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration of S88-driven Rac change limited\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped a second Abl-interaction tyrosine (Y398) in the SH3 domain, showing combined Y213/Y398 phosphorylation strengthens Abl binding and stimulates Mena phosphorylation.\",\n      \"evidence\": \"Mutagenesis, in vitro kinase and binding assays\",\n      \"pmids\": [\"21320496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular significance of dual-site phosphorylation not validated in vivo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a conserved axon-guidance role through direct ABI-1/MIG-10 (lamellipodin) binding placing ABI-1/WAVE downstream of MIG-10 in netrin and slit pathways.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, domain mapping, C. elegans epistasis, mammalian lamellipodia assay\",\n      \"pmids\": [\"23209429\", \"23028145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian in vivo guidance role not directly tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed ABI1 mediates smooth muscle contraction by linking c-Abl/CAS to N-WASP activation and actin polymerization independent of myosin light chain phosphorylation.\",\n      \"evidence\": \"Co-IP, lentiviral RNAi, FRET N-WASP sensor, actin polymerization and contraction assays\",\n      \"pmids\": [\"23740246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of complex assembly during contraction not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected tyrosine-phosphorylated ABI1 (pY435) to invasion, localizing it to matrix-degradation sites in an Abl-dependent manner.\",\n      \"evidence\": \"RNAi knockdown, matrix degradation assay, STI571 treatment, immunofluorescence\",\n      \"pmids\": [\"24913355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase site specificity for Y435 not biochemically isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined how ABI1 routes the WAVE2 complex toward lamellipodia vs invadopodia, with a proline-rich/SH3 linker required for c-Abl binding and Abl-mediated WAVE2 phosphorylation.\",\n      \"evidence\": \"Domain deletion, Co-IP, imatinib/siRNA, morphological assays; tri-complex domain mapping with TAT peptides\",\n      \"pmids\": [\"26428302\", \"31488087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch between protrusion types not quantitatively dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ABI1 as a tumor-suppressive negative regulator of hematopoietic SFK/STAT3/NF-\\u03baB signaling, with bone-marrow KO producing a myeloproliferative/myelofibrosis-like disease.\",\n      \"evidence\": \"Conditional KO mouse, bone marrow transplantation, kinase and signaling assays, patient sample corroboration\",\n      \"pmids\": [\"30213875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target through which ABI1 restrains SFKs unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PTEN as the phosphatase that dephosphorylates ABI1 Y213/S216 to trigger calpain-dependent degradation, downregulating the WAVE complex and driving epithelial polarization and, when lost, EMT.\",\n      \"evidence\": \"Phospho-IP/MS, PTEN mutant reconstitution, calpain inhibitor rescue, embryoid body and breast cancer EMT assays\",\n      \"pmids\": [\"32673396\", \"32728066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain cleavage site on ABI1 not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined leading-edge mechanics, showing ABI1 recruits profilin-1, c-Abl and N-WASP to the lamellipodial tip under integrin \\u03b21/c-Abl control, and that CRISPR KO blocks Bcr-Abl ERK/PI3K signaling and leukemogenesis.\",\n      \"evidence\": \"shRNA/CRISPR KO, live imaging, Co-IP, leading-edge localization, in vivo leukemogenesis\",\n      \"pmids\": [\"32606387\", \"32276588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct profilin-1 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ubiquitin-mediated turnover via CBLC that degrades ABI1 to activate ERK signaling in colorectal cancer, complementing calpain proteolysis as a degradation route.\",\n      \"evidence\": \"Ubiquitination assay, Co-IP, gain/loss-of-function, ERK analysis, xenograft\",\n      \"pmids\": [\"38743987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site(s) on ABI1 not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved a spectrin-tethered reservoir mechanism whereby pathogen-induced calpain cleavage releases cortical ABI1 to bind EPS8 and activate its actin-capping activity for protrusion-based cell-to-cell spread.\",\n      \"evidence\": \"Conditional KO mouse, Co-IP, calpain inhibition, Ca2+ imaging, protrusion/spread assay during Listeria infection\",\n      \"pmids\": [\"41974702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of spectrin-tethered ABI1 pool beyond infection unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ABI1's many phosphorylation sites, splice isoforms, and competing proteolysis routes are integrated to select between WAVE-driven protrusion, N-WASP-driven trafficking, nuclear transcription, and kinase regulation in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length ABI1 in its complexes\", \"Quantitative rules governing isoform/PTM-dependent partner choice undefined\", \"In vivo coordination of cytoplasmic vs nuclear ABI1 pools unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 5, 6, 20, 22, 33]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 7, 8, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 23, 30, 47]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 17, 39]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 8, 39, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 8, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 15, 30]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 13, 14, 47]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 28, 37, 44]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 20, 35, 36, 50]}\n    ],\n    \"complexes\": [\n      \"WAVE regulatory complex (WAVE2-ABI1-NAP1-PIR121)\",\n      \"EPS8-ABI1-SOS1 tri-complex\"\n    ],\n    \"partners\": [\n      \"WAVE2\",\n      \"EPS8\",\n      \"SOS1\",\n      \"ABL1\",\n      \"WASL\",\n      \"PIK3R1\",\n      \"ITGA4\",\n      \"SHANK3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":9,"faith_pct":88.88888888888889}}