Affinage

ABI2

Abl interactor 2 · UniProt Q9NYB9

Length
513 aa
Mass
55.7 kDa
Annotated
2026-04-28
43 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABI2 is an adaptor/scaffold protein that functions as a core component of the WAVE regulatory complex (WRC) downstream of Rac1, coupling upstream signaling to Arp2/3-dependent actin polymerization, lamellipodia formation, and cell migration. ABI2 binds the c-Abl tyrosine kinase SH3 domain via proline-rich sequences and serves as both a negative regulator and a phosphorylation substrate of c-Abl, with Pak2-mediated phosphorylation of c-Abl switching its binding partner from ABI2 to Crk (PMID:7590236, PMID:18161990). PIM1 phosphorylates ABI2 at Ser183 to stabilize the protein and enhance WRC assembly and actin protrusive activity, while CBLC-mediated ubiquitination targets ABI2 for degradation (PMID:37042842, PMID:38937761). In vivo, ABI2 is essential for neuronal migration, dendritic spine morphogenesis, adherens junction integrity, and learning/memory, and de novo SH3-domain missense variants cause a neurodevelopmental disorder featuring intellectual disability, epilepsy, and corpus callosum abnormalities (PMID:15572692, PMID:40475134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Establishing that ABI2 is a direct binding partner and substrate of c-Abl, and that disruption of specific binding interfaces activates Abl transforming capacity, identified ABI2 as a dual regulator–effector of Abl signaling.

    Evidence Yeast two-hybrid, in vitro binding, co-immunoprecipitation, kinase assay, and transformation assay

    PMID:7590236

    Open questions at the time
    • Endogenous stoichiometry and dynamics of the ABI2–Abl complex were not measured
    • In vivo physiological relevance of the regulatory interaction was not tested
  2. 2000 Medium

    Demonstrating ABI2 expression in the developing nervous system, enrichment in synaptosomes and growth cones, and requirement for Rac-dependent cytoskeletal remodeling linked ABI2 to neuronal actin dynamics.

    Evidence Subcellular fractionation, immunohistochemistry, and phosphorylation analysis in developing brain

    PMID:10995551

    Open questions at the time
    • Direct actin-regulatory mechanism was not identified
    • Functional relationship with WAVE complex was not established
  3. 2004 High

    Genetic ablation of Abi2 in mice revealed essential roles in lens fiber cell migration, cortical neuronal migration, dendritic spine morphogenesis, and learning/memory, and connected ABI2 to adherens junction formation and WAVE complex stability.

    Evidence Abi2 knockout mouse, RNAi, immunofluorescence, behavioral testing, histology

    PMID:15572692

    Open questions at the time
    • Molecular mechanism by which ABI2 stabilizes WAVE at adherens junctions was undefined
    • Relative contributions of ABI1 vs ABI2 in overlapping tissues were not resolved
  4. 2007 High

    Identifying Pak2-mediated phosphorylation of c-Abl at Ser637/638 as a switch that disrupts ABI2 SH3-domain binding while promoting Crk binding revealed a phosphorylation-dependent mechanism for toggling Abl effector specificity.

    Evidence In vitro kinase assay, site-directed mutagenesis, binding assays

    PMID:18161990

    Open questions at the time
    • In vivo relevance of the Pak2-triggered ABI2/Crk switch was not validated
    • Whether other kinases similarly regulate this switch was not explored
  5. 2012 High

    Showing that the WAVE2–ABI2 complex is phosphorylated by Abl and Cdk5 to control growth cone dynamics and the multipolar-to-bipolar neuronal transition placed ABI2 at a signaling node integrating kinase cascades with cortical neuron migration.

    Evidence Time-lapse imaging, in utero electroporation, phospho-mutagenesis

    PMID:22617848

    Open questions at the time
    • Structural basis for how phospho-WAVE2 alters ABI2-dependent actin dynamics was unknown
    • Contribution of ABI2 independent of WAVE2 was not tested
  6. 2022 Medium

    Discovery that PRR16 binds ABI2 and that ABI2 depletion increases ABL1 Y412 phosphorylation reinforced ABI2's role as an endogenous negative regulator of ABL1 kinase activity and linked its disruption to epithelial–mesenchymal transition.

    Evidence Co-immunoprecipitation, gene silencing, Western blot for ABL1 phosphorylation

    PMID:35719027

    Open questions at the time
    • Mechanism of PRR16-mediated relief of ABI2 inhibition was indirect
    • Not independently confirmed by a second group
  7. 2022 Medium

    Identifying ABI2 as a recruiter and co-activator of the transcription factor MEOX2 at the KLF4 and NANOG promoters revealed an unexpected nuclear/transcriptional function of ABI2 in maintaining cancer stem cell properties.

    Evidence Co-immunoprecipitation, ChIP, luciferase reporter, xenograft model in hepatocellular carcinoma

    PMID:36017822

    Open questions at the time
    • Nuclear localization and chromatin-binding mechanism of ABI2 were not characterized
    • Finding from a single lab in one cancer type
  8. 2023 High

    Identification of ABI2 as a direct PIM1 substrate phosphorylated at Ser183 established a mechanism by which hypoxia-induced kinase signaling stabilizes ABI2 protein, promotes WRC assembly, and drives actin protrusion and cell motility.

    Evidence Unbiased proteomic screen, in vitro kinase assay, phospho-mutagenesis, WRC co-immunoprecipitation, protrusion and invasion assays

    PMID:37042842

    Open questions at the time
    • Whether PIM1 phosphorylation of ABI2 occurs in non-cancer physiological contexts is unknown
    • Structural basis for how Ser183 phosphorylation stabilizes ABI2 and promotes WRC assembly was not resolved
  9. 2024 Medium

    Demonstrating that CBLC E3 ubiquitin ligase mediates ubiquitination and degradation of ABI2, and that ABI2 interacts with RAC1 to restrain PI3K/Akt signaling, defined a proteolytic control mechanism governing ABI2 abundance and its tumor-suppressive functions.

    Evidence Ubiquitination assay, co-immunoprecipitation with RAC1, RNA-seq, functional assays in TNBC cells

    PMID:38937761

    Open questions at the time
    • Direct ubiquitination sites on ABI2 were not mapped
    • Interplay between PIM1-mediated stabilization and CBLC-mediated degradation was not explored
  10. 2025 Medium

    Identification of recurrent de novo SH3-domain missense variants (especially p.Tyr491Cys) in eight unrelated individuals with intellectual disability, epilepsy, and white matter abnormalities established ABI2 as a Mendelian neurodevelopmental disease gene.

    Evidence (preprint) Exome sequencing and clinical phenotyping across 8 unrelated individuals

    PMID:40475134

    Open questions at the time
    • No in vitro or cellular functional validation of variant pathogenicity has been performed
    • Whether variants act via loss-of-function, gain-of-function, or dominant-negative mechanism is unknown
    • Not yet peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ABI2's cytoplasmic actin-regulatory functions relate to its reported transcriptional co-activator roles, and the precise structural consequences of disease-causing SH3 variants on WRC assembly and Abl regulation, remain unresolved.
  • No high-resolution structure of ABI2 in complex with WRC or Abl is available
  • Nuclear function of ABI2 lacks independent confirmation
  • Functional consequence of the recurrent Tyr491Cys variant on protein interactions is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 2
Partners
ABL1CBLCHHEXMEOX2PIM1PRR16RAC1WAVE2
Complex memberships
WAVE regulatory complex (WRC)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 ABI2 (Abi-2) was identified as a protein that binds specifically to both the SH3 domain and carboxy-terminal sequences of c-Abl tyrosine kinase via yeast two-hybrid and confirmed in vitro and in vivo binding; Abi-2 contains proline-rich sequences critical for SH3 binding and is a substrate for c-Abl tyrosine kinase phosphorylation. Expression of an Abi-2 mutant lacking the Abl SH3-binding sequences but retaining carboxyl-terminal binding activates c-Abl transforming capacity, indicating a dual role as regulator and effector of c-Abl. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, kinase substrate assay, functional transformation assay Genes & development High 7590236
2000 Abi-1 and Abi-2 proteins are expressed in the developing nervous system, undergo age-dependent changes in phosphorylation, are concentrated in synaptosomes and growth cone particles, and are required for Rac-dependent cytoskeletal reorganization in response to growth factor stimulation. Subcellular fractionation, immunohistochemistry, in situ hybridization, Western blot with phosphorylation analysis Molecular and cellular neurosciences Medium 10995551
2004 Homozygous deletion of murine abi2 causes defective lens fiber cell migration and orientation, impaired neuronal migration in neocortex and hippocampus, abnormal dendritic spine morphogenesis, and severe learning/memory deficits. Abi2 localizes to adherens junctions in the developing lens and nascent epithelial cell adherens junctions. RNAi-mediated downregulation of Abi impairs adherens junction formation and correlates with downregulation of WAVE actin-nucleation promoting factor. Knockout mouse, RNA interference, immunofluorescence localization, behavioral testing, histology Molecular and cellular biology High 15572692
2007 Phosphorylation of c-Abl at serines 637 and 638 by Pak2 kinase dramatically reduces ABI2 SH3-domain binding (~90% reduction) to the PxxP motif of c-Abl, while simultaneously increasing binding of Crk to c-Abl and enhancing c-Abl-mediated Crk phosphorylation, revealing a mechanism for switch between ABI2 and Crk association with c-Abl. In vitro kinase assay, site-directed mutagenesis, binding assay, co-immunoprecipitation Biochemistry High 18161990
2012 WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-to-bipolar transition of migrating neurons and initiation of glia-guided migration in the neocortex. Abl kinase and Cdk5 phosphorylate WAVE2 (at Y150 and S137) via the WAVE2-Abi2 complex to regulate these growth cone activities. Time-lapse imaging, lattice assays, in utero electroporation, phospho-mutagenesis Cerebral cortex High 22617848
2022 ABI2 recruits and directly interacts with the transcription factor MEOX2, which binds to the KLF4 and NANOG promoter regions to activate their transcription, thereby maintaining cancer stem cell properties in hepatocellular carcinoma. Co-immunoprecipitation, ChIP, luciferase reporter assay, knockdown/overexpression functional studies, xenograft model Liver international Medium 36017822
2022 PRR16/Largen binds to ABI2, and knockdown of ABI2 or overexpression of PRR16 increases phosphorylation of ABL1 kinase at Y412, suggesting ABI2 inhibits ABL1 kinase activity and PRR16 induces EMT by interfering with ABI2's inhibition of ABL1. Co-immunoprecipitation, gene silencing, Western blot for ABL1 phosphorylation, migration/invasion assays Biomolecules & therapeutics Medium 35719027
2023 PIM1 kinase phosphorylates ABI2 at Ser183, which increases ABI2 protein stability and enhances WAVE regulatory complex (WRC) formation, resulting in increased actin protrusive activity and cell motility. ABI2 is identified as a PIM1 substrate by unbiased proteomic screen, and hypoxia-induced protrusion is dependent on ABI2. Unbiased proteomic screen, in vitro kinase assay, phospho-mutagenesis, WRC co-immunoprecipitation, protrusion assay, in vivo invasion assay The Journal of cell biology High 37042842
2024 ABI2 acts as a co-activator of the transcription factor HHEX, and the HHEX-ABI2 complex upregulates SLC17A9 transcription to promote hepatocellular carcinoma cancer stem cell properties and tumorigenesis. Co-immunoprecipitation, ChIP, luciferase reporter assay, knockdown/overexpression, tumor xenograft Journal of translational medicine Medium 38844969
2024 CBLC E3 ubiquitin ligase increases ubiquitination-dependent degradation of ABI2 protein; ABI2 interacts with Rho GTPase RAC1 and inhibits the PI3K/Akt signaling pathway, controlling cell cycle and suppressing TNBC cell migration, invasion, and proliferation. Ubiquitination assay, co-immunoprecipitation, RNA-seq, Western blot, knockdown/overexpression functional assays Cancer cell international Medium 38937761
2025 De novo heterozygous missense variants in ABI2 SH3 domain (recurrent p.Tyr491Cys in 6/8 individuals) cause a neurodevelopmental disorder with intellectual disability, epilepsy, corpus callosum hypoplasia, and white matter abnormalities, establishing ABI2 as a causative gene for a human neurodevelopmental syndrome. Exome sequencing, clinical phenotyping in 8 unrelated individuals with de novo variants medRxiv (preprint) / bioRxivpreprint Medium 40475134

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The Arabidopsis ABSCISIC ACID-INSENSITIVE2 (ABI2) and ABI1 genes encode homologous protein phosphatases 2C involved in abscisic acid signal transduction. The Plant cell 551 9165752
2001 The ABI1 and ABI2 protein phosphatases 2C act in a negative feedback regulatory loop of the abscisic acid signalling pathway. The Plant journal : for cell and molecular biology 448 11208021
2001 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. The Plant cell 382 11701885
1997 Differential abscisic acid regulation of guard cell slow anion channels in Arabidopsis wild-type and abi1 and abi2 mutants. The Plant cell 330 9090884
2004 Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix. Cell death and differentiation 314 15195070
2003 A novel domain in the protein kinase SOS2 mediates interaction with the protein phosphatase 2C ABI2. Proceedings of the National Academy of Sciences of the United States of America 271 14504388
1995 Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes & development 248 7590236
2012 FERONIA receptor kinase pathway suppresses abscisic acid signaling in Arabidopsis by activating ABI2 phosphatase. Proceedings of the National Academy of Sciences of the United States of America 227 22908257
1999 Arabidopsis abi1-1 and abi2-1 phosphatase mutations reduce abscisic acid-induced cytoplasmic calcium rises in guard cells. The Plant cell 210 10488243
2016 FERONIA interacts with ABI2-type phosphatases to facilitate signaling cross-talk between abscisic acid and RALF peptide in Arabidopsis. Proceedings of the National Academy of Sciences of the United States of America 204 27566404
1998 ABI2, a second protein phosphatase 2C involved in abscisic acid signal transduction in Arabidopsis. FEBS letters 175 9468303
2015 Nitrate sensing and uptake in Arabidopsis are enhanced by ABI2, a phosphatase inactivated by the stress hormone abscisic acid. Science signaling 158 25943353
2001 The sensitivity of ABI2 to hydrogen peroxide links the abscisic acid-response regulator to redox signalling. Planta 133 11882947
2017 Abscisic Acid Signaling Inhibits Brassinosteroid Signaling through Dampening the Dephosphorylation of BIN2 by ABI1 and ABI2. Molecular plant 132 29275167
2004 ABI2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory. Molecular and cellular biology 123 15572692
2000 Localization and phosphorylation of Abl-interactor proteins, Abi-1 and Abi-2, in the developing nervous system. Molecular and cellular neurosciences 63 10995551
1998 Molecular cloning in Arabidopsis thaliana of a new protein phosphatase 2C (PP2C) with homology to ABI1 and ABI2. Plant molecular biology 62 9862504
2004 The ABI2-dependent abscisic acid signalling controls HrpN-induced drought tolerance in Arabidopsis. Planta 51 15599761
2009 AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model. Human molecular genetics 49 19414486
2011 Molecular and physiological characterization of the Arabidopsis thaliana Oxidation-related Zinc Finger 2, a plasma membrane protein involved in ABA and salt stress response through the ABI2-mediated signaling pathway. Plant & cell physiology 48 22121246
2000 The genes ABI1 and ABI2 are involved in abscisic acid- and drought-inducible expression of the Daucus carota L. Dc3 promoter in guard cells of transgenic Arabidopsis thaliana (L.) Heynh. Planta 45 10872217
2022 ABI2-mediated MEOX2/KLF4-NANOG axis promotes liver cancer stem cell and drives tumour recurrence. Liver international : official journal of the International Association for the Study of the Liver 32 36017822
2011 Identification of an important site for function of the type 2C protein phosphatase ABI2 in abscisic acid signalling in Arabidopsis. Journal of experimental botany 32 21885535
2002 In search of a function for the E3B1/Abi2/Argbp1/NESH family (Review). International journal of molecular medicine 30 12011975
2020 Downregulation of ABI2 expression by EBV-miR-BART13-3p induces epithelial-mesenchymal transition of nasopharyngeal carcinoma cells through upregulation of c-JUN/SLUG signaling. Aging 24 31907338
2010 skn-1-Dependent and -independent regulation of aip-1 expression following metabolic stress in Caenorhabditis elegans. Molecular and cellular biology 19 20351174
2021 TMK4 receptor kinase negatively modulates ABA signaling by phosphorylating ABI2 and enhancing its activity. Journal of integrative plant biology 18 33811744
2012 WAVE2-Abi2 complex controls growth cone activity and regulates the multipolar-bipolar transition as well as the initiation of glia-guided migration. Cerebral cortex (New York, N.Y. : 1991) 17 22617848
2007 Phosphorylation of c-Abl by protein kinase Pak2 regulates differential binding of ABI2 and CRK. Biochemistry 15 18161990
2023 PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion. The Journal of cell biology 12 37042842
2017 A Novel RNA-Binding Protein Involves ABA Signaling by Post-transcriptionally Repressing ABI2. Frontiers in plant science 12 28174577
2022 PRR16/Largen Induces Epithelial-Mesenchymal Transition through the Interaction with ABI2 Leading to the Activation of ABL1 Kinase. Biomolecules & therapeutics 9 35719027
2020 Association of Abl interactor 2, ABI2, with platelet/lymphocyte ratio in patients with renal cell carcinoma: A pilot study. International journal of experimental pathology 6 32496656
2016 TIS21/BTG2 inhibits doxorubicin-induced stress fiber-vimentin networks via Nox4-ROS-ABI2-DRF-linked signal cascade. Cellular signalling 6 27932314
2022 Na-AIP-1 secreted by human hookworms suppresses collagen-induced arthritis. Inflammopharmacology 5 35031905
2020 miR-25 expression is upregulated in pancreatic ductal adenocarcinoma and promotes cell proliferation by targeting ABI2. Experimental and therapeutic medicine 5 32266037
2024 The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC. Journal of translational medicine 4 38844969
2024 Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway. Cancer cell international 3 38937761
2025 The role of ABI2 in modulating nuclear proteins: Therapeutic implications for NUP54 and NUP153 in TNBC. Advances in protein chemistry and structural biology 2 39843146
2025 Ethylene antagonizes ABA responses in stomatal movement and seed germination by upregulating ABI1 and ABI2 at both the transcript and protein levels. The Plant journal : for cell and molecular biology 1 40811817
2013 Age and dark rearing bidirectionally regulate the level and laminar pattern of expression of Abelson interacting protein 2 (Abi-2): a novel candidate visual cortical plasticity gene. Journal of molecular neuroscience : MN 1 23828391
2025 Missense ABI2 variants linked to a neurodevelopmental disorder with intellectual disability, epilepsy, hypoplasia of the corpus callosum, and white matter abnormalities. medRxiv : the preprint server for health sciences 0 40475134
2025 Arsenic Sulfide Induces Apoptosis in Myelodysplastic Neoplasm Cells Through the Suppression of ABI2. Biological procedures online 0 41366287