Affinage

BAIAP2

BAR/IMD domain-containing adapter protein 2 · UniProt Q9UQB8

Length
552 aa
Mass
60.9 kDa
Annotated
2026-06-09
100 papers in source corpus 48 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAIAP2 (IRSp53) is a multidomain scaffold that couples plasma-membrane deformation to actin polymerization, acting as the central node linking Rho-family GTPase signaling to the formation of filopodia, lamellipodia, and other membrane protrusions (PMID:11130076, PMID:11696321, PMID:17371834). Its N-terminal I-BAR (IMD) domain binds PI(4,5)P2-rich membranes and deforms them into outward (negative-curvature) protrusions opposite to classical BAR domains, and this membrane-deforming activity—rather than actin bundling per se—is the critical determinant of filopodium induction (PMID:17371834, PMID:17003044); biophysical reconstitution shows the I-BAR dimer senses negative membrane curvature in a tension-dependent manner (PMID:26469246). The C-terminal SH3 domain recruits a competing repertoire of actin regulators—WAVE2, Mena/VASP, Eps8, N-WASP, mDia1, and SPIN90—downstream of activated Rac and Cdc42, with GTPase binding relieving an intramolecular autoinhibition to license SH3 engagement (PMID:11130076, PMID:11696321, PMID:15289329, PMID:18448434, PMID:22179776). IRSp53 optimizes Rac/PIP3-dependent WAVE2–Arp2/3 activation on membranes (PMID:16702231) and, when clustered on PIP2 membranes, recruits VASP to drive processive actin elongation that builds filopodium-like protrusions in fully reconstituted systems (PMID:36240267, PMID:24076653). Its activity is tuned by inhibitory phosphorylation-dependent 14-3-3 binding, which blocks membrane and Cdc42/effector engagement and is set by kinases including AMPK (PMID:30696821, PMID:19933840, PMID:30893014). At excitatory synapses, IRSp53 is incorporated into PSD condensates through multivalent interactions with Shank and PSD-95 and limits NMDA receptor density and synaptic plasticity; its loss in mice enhances NMDAR-mediated transmission and produces social deficits reversible by NMDAR/mGluR5 antagonism (PMID:19208628, PMID:35819332, PMID:19193906, PMID:25622145). The protein also serves morphogenetic roles in epithelial lumen formation and cortical neuronal migration, and is exploited by pathogens—bridging EHEC Tir/EspFU to actin pedestals and shaping HIV-1 membrane curvature during budding (PMID:32665580, PMID:38149472, PMID:19286134, PMID:34114563). A de novo I-BAR domain variant (p.Arg29Trp) that abolishes membrane localization causes neurodevelopmental defects, establishing a direct link between IRSp53 membrane targeting and cortical development (PMID:38149472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 High

    Established IRSp53 as the physical bridge connecting active Rac to the WAVE actin nucleation machinery, defining its core role as a GTPase-to-actin adaptor.

    Evidence Co-IP and domain-binding assays reconstituting a Rac–IRSp53–WAVE trimolecular complex driving membrane ruffling

    PMID:11130076

    Open questions at the time
    • Did not resolve how membrane binding integrates with this complex
    • Structural basis of the Rac-binding region not defined
  2. 2001 High

    Showed that Cdc42 binding relieves an intramolecular autoinhibition to license SH3-mediated effector recruitment, explaining GTPase-dependent switching toward filopodia.

    Evidence Affinity chromatography, Co-IP, dominant-negative expression and filopodia assays in fibroblasts identifying the IRSp53–Mena complex

    PMID:11696321

    Open questions at the time
    • Atomic mechanism of autoinhibition relief not defined
    • Quantitative competition among SH3 partners not addressed
  3. 2002 High

    Identified Shank/ProSAP as a postsynaptic SH3 partner of IRSp53, anchoring it to the PSD and revealing Cdc42-regulated synaptic localization.

    Evidence Yeast two-hybrid, Co-IP from rat brain membranes, and mutational mapping; cellular redistribution assays in HEK cells

    PMID:12421375 PMID:12504591

    Open questions at the time
    • Functional consequence at synapses not yet measured
    • Did not establish PSD condensate context
  4. 2004 High

    Defined the IRSp53–Eps8 complex at the leading edge as a positive amplifier of Rac signaling, linking membrane protrusion to GEF activation.

    Evidence Co-IP, direct binding, FRET in live cells, and invasion/motility assays

    PMID:15289329

    Open questions at the time
    • Did not resolve competition with other SH3 partners
    • In vivo relevance of leading-edge complex untested
  5. 2005 High

    Crystal structure of the I-BAR (IMD) domain revealed a zeppelin-shaped coiled-coil dimer and tied basic-tip residues to actin bundling and filopodia induction.

    Evidence X-ray crystallography, analytical ultracentrifugation, in vitro actin bundling, and filopodia assays with mutagenesis

    PMID:15635447

    Open questions at the time
    • Membrane-deformation role of the domain not yet separated from actin bundling
    • Relative contribution of bundling vs curvature unresolved at this stage
  6. 2007 High

    Resolved the central mechanism by showing the I-BAR domain binds PI(4,5)P2 and generates outward (negative) membrane curvature, the activity critical for filopodium induction—distinct from actin bundling.

    Evidence In vitro PI(4,5)P2 liposome tubulation, electron microscopy, mutagenesis separating activities, and cellular filopodia assays

    PMID:17003044 PMID:17371834

    Open questions at the time
    • How membrane curvature is coupled in time to actin assembly not yet reconstituted
    • Tension dependence of curvature activity not addressed
  7. 2008 High

    Demonstrated that the I-BAR domain alone makes actin-free protrusions while SH3 partners (N-WASP, Mena/VASP) are required for full filopodia, partitioning the membrane-shaping and actin-elongating functions.

    Evidence Co-IP and reconstitution in N-WASP and Mena/VASP knockout fibroblasts with domain mutants

    PMID:18448434

    Open questions at the time
    • Did not identify which elongation mechanism dominates in vivo
    • Regulation of partner selection unresolved
  8. 2009 High

    Genetic knockout established IRSp53 as a negative regulator of NMDA receptor function and synaptic plasticity, embedding it in postsynaptic Shank/Eps8 competition that controls PSD composition.

    Evidence IRSp53 KO mice with electrophysiology (AMPA/NMDA ratio, LTP), immuno-EM of PSD, and competitive binding assays

    PMID:19193906 PMID:19208628

    Open questions at the time
    • Molecular basis of NMDAR restriction not fully defined
    • Link to behavior not yet established at this stage
  9. 2009 High

    Revealed multiple negative regulators (14-3-3, Kank, synaptopodin) that selectively gate IRSp53 toward Rac- or Cdc42-driven protrusions, establishing combinatorial control of its output.

    Evidence Phospho-site mapping, Co-IP competition, RNAi, and live-cell filopodia/lamellipodia assays

    PMID:17569780 PMID:19171758 PMID:19933840

    Open questions at the time
    • Kinases setting 14-3-3 sites not yet identified
    • Structural basis of 14-3-3 inhibition unresolved
  10. 2009 High

    Showed IRSp53 is the host factor coupling EHEC Tir to EspFU and N-WASP for actin pedestal assembly, extending its adaptor role to pathogen-driven actin polymerization.

    Evidence Co-IP, direct binding, IRSp53 KO cells, and immunofluorescence colocalization in actin pedestals

    PMID:19286134

    Open questions at the time
    • Structural recognition of the Tir NPY motif not yet defined (resolved later)
    • Generality to other I-BAR proteins untested here
  11. 2011 High

    Crystallography of the I-BAR–Tir NPY peptide complex defined a conserved surface binding site, providing structural detail for pathogen hijacking of IRSp53.

    Evidence X-ray crystallography with mutagenesis and in vivo binding validation

    PMID:21893288

    Open questions at the time
    • Whether host ligands use the same I-BAR surface not addressed
  12. 2013 High

    Reconstitution revealed the GTPase switch at the actin barbed end: IRSp53 inhibits barbed-end growth until CDC42 relieves it and converts IRSp53 into a VASP-clustering factor driving processive elongation, with in vivo wound-healing requirement.

    Evidence In vitro actin polymerization, single-molecule TIRF, liposome binding, and IRSp53 KO mouse wound-healing assays

    PMID:24076653

    Open questions at the time
    • Stoichiometry of VASP clustering on membranes not defined here
    • How phosphoregulation intersects this switch not addressed
  13. 2015 High

    Quantified the biophysics of I-BAR curvature sensing, showing tension-dependent, non-monotonic sorting and density-dependent domain formation on membrane tubes.

    Evidence Protein encapsulation in GUVs connected to membrane nanotubes with theoretical modeling

    PMID:26469246

    Open questions at the time
    • Coupling of sensing to actin assembly not reconstituted in this system
    • Full-length protein behavior not yet tested here
  14. 2015 High

    Linked elevated NMDAR activity to behavioral deficits by showing NMDAR/mGluR5 antagonists rescue social impairments in IRSp53 KO mice, establishing causal relevance to circuit function.

    Evidence IRSp53 KO mice with behavioral testing, electrophysiology, and pharmacological rescue (memantine/MPEP)

    PMID:25622145

    Open questions at the time
    • Molecular mechanism limiting NMDAR density not fully defined
    • Cell-type specificity of the deficit unresolved
  15. 2019 High

    Defined the structural and conformational basis of 14-3-3 inhibition and identified AMPK as a kinase setting these sites, providing a metabolic input that suppresses filopodia and chemotaxis.

    Evidence Phosphoproteomics, crystallography of 14-3-3:phosphopeptide complexes, FRET conformational sensors, and pharmacological AMPK modulation with site mutants

    PMID:30696821 PMID:30893014

    Open questions at the time
    • Full set of physiological kinases at these sites not enumerated
    • Dynamics of 14-3-3 release in cells not measured
  16. 2020 High

    Extended IRSp53 function to epithelial morphogenesis, showing it controls lumen formation and apical polarity via RAB35 and EPS8 in renal tubulogenesis.

    Evidence IRSp53 KO mouse, CLEM, Co-IP, and RAB35 activity assays

    PMID:32665580

    Open questions at the time
    • Mechanism linking membrane curvature to RAB35 regulation unresolved
    • Whether actin assembly is required not fully separated
  17. 2021 High

    Demonstrated that the I-BAR domain shapes HIV-1 membrane curvature during budding, with Gag enriching at I-BAR-induced curvature, identifying a viral exploitation of IRSp53 curvature activity.

    Evidence siRNA knockdown, single-molecule localization microscopy, GUV curvature assays, and proteomics of purified virions

    PMID:34114563

    Open questions at the time
    • Direct Gag–IRSp53 contact not defined
    • Whether actin machinery contributes to budding unresolved
  18. 2022 High

    Achieved full reconstitution of IRSp53-driven filopodium-like protrusions, showing PIP2-dependent self-clustering recruits VASP for local actin assembly at dynamic membrane regions.

    Evidence In vitro reconstitution on GUVs and supported bilayers, membrane nanotube pulling, TIRF, live-cell imaging, and MD simulation

    PMID:36240267

    Open questions at the time
    • Regulatory inputs not included in minimal system
    • Quantitative threshold for clustering in cells not defined
  19. 2022 High

    Showed IRSp53 partitions into PSD liquid-liquid phase-separated condensates via PSD-95/Shank3 bridging and links these condensates to membrane-associated actin bundling required for synapse maturation.

    Evidence In vitro droplet/PSD reconstitution, actin bundling assays on membranes, and mutant expression in mouse cortical neurons

    PMID:35819332

    Open questions at the time
    • How condensate incorporation tunes NMDAR density mechanistically not resolved
    • In vivo relevance of phase separation untested
  20. 2024 High

    Connected IRSp53 to neurodevelopmental disease by showing a de novo I-BAR variant (p.Arg29Trp) abolishes membrane localization and disrupts cortical neuronal migration and morphogenesis.

    Evidence In utero electroporation knockdown and variant rescue, spatial transcriptomics, and membrane localization assays in developing mouse cortex

    PMID:38149472

    Open questions at the time
    • Human clinical spectrum not defined from this study
    • Downstream actin pathway altered by the variant not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing inputs (GTPases, phosphorylation/14-3-3, SH3 partner competition, membrane tension, and phase separation) are integrated to determine when and where IRSp53 builds a specific protrusion type in vivo remains unresolved.
  • No unified model coupling membrane tension, GTPase state, and phosphoregulation in living cells
  • Quantitative rules for SH3-partner selection in different cell types unknown
  • Mechanism by which IRSp53 restricts synaptic NMDAR density not molecularly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 4 GO:0008289 lipid binding 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005856 cytoskeleton 4 GO:0005886 plasma membrane 4 GO:0005654 nucleoplasm 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3
Partners
BAI1DIAPH1DLG4ENAHEPS8SHANK1WASF2WASL
Complex memberships
IRSp53–Eps8 complexPSD (PSD-95/Shank) condensateRac–IRSp53–WAVE2 complexWAVE2/Abi1–IRSp53 complex

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Activated Rac binds to the N-terminal domain of IRSp53, and the C-terminal SH3 domain of IRSp53 binds to WAVE, forming a trimolecular Rac–IRSp53–WAVE complex that is essential for Rac-induced membrane ruffling. Co-immunoprecipitation, ectopic expression, domain-binding assays Nature High 11130076
2001 Cdc42 binds to a partial CRIB motif in IRSp53, relieving an intramolecular autoinhibitory interaction between the CRIB-containing central region and the N-terminal domain, thereby allowing the SH3 domain to recruit Mena; the resulting IRSp53–Mena complex promotes filopodia formation. Affinity chromatography, co-immunoprecipitation, dominant-negative expression, filopodia formation assay in fibroblasts Current Biology High 11696321
1999 The SH3 domain of BAIAP2/IRSp53 directly binds to a proline-rich cytoplasmic fragment of BAI1 (brain-specific angiogenesis inhibitor 1), and co-expression with BAI1 recruits BAIAP2 to the cytoplasmic membrane. Yeast two-hybrid, in vitro binding assay, double-color immunofluorescence in COS-7 cells Cytogenetics and Cell Genetics Medium 10343108
2000 The proline-rich FH1 domain of mDia1 binds the SH3 domain of IRSp53/BAIAP2 in a GTP-Rho-dependent manner, identifying IRSp53 as a downstream effector of mDia1. Pulldown assay, co-immunoprecipitation with GTP-Rho Biochemical and Biophysical Research Communications Medium 10814512
2002 The SH3 domain of IRSp53 interacts with a proline-rich sequence in ProSAP/Shank family members, and the IRSp53–Shank complex is co-immunoprecipitated from rat brain membranes; active Cdc42 regulates coprecipitation of IRSp53 with Shank1. Yeast two-hybrid, Co-IP from rat brain, mutational analysis, co-expression in COS cells Journal of Neurochemistry High 12421375 12504591
2002 The SH3 domain of IRSp53 interacts with proline-rich residues 911–940 of Shank1; co-expression of Shank1 with IRSp53 in HEK cells prevents IRSp53 targeting to filopodia, and this redistribution is regulated by active Cdc42. Yeast two-hybrid, overlay assay, co-expression in HEK cells, pulldown with GTPase Molecular and Cellular Neurosciences Medium 12504591
2003 IRSp53 localizes specifically to the tips of protruding lamellipodia and filopodia via its N-terminal Rac-binding domain, and co-localizes with WAVE2 at these sites during protrusion. Live-cell imaging of EGFP-tagged IRSp53 and DsRed-WAVE2, antibody labeling, deletion mutant analysis Journal of Cell Science High 12734400
2004 IRSp53 directly binds Eps8 via its SH3 domain and the N-terminal proline-rich region of Eps8; the IRSp53–Eps8 complex forms at the leading edge of motile cells and synergistically activates Rac by reinforcing formation of the Eps8/Abi-1/Sos-1 GEF complex. Co-immunoprecipitation, direct binding assay, FRET analysis in live cells, invasion/motility assays Cancer Research High 15289329
2005 The crystal structure of the IRSp53 IMD (I-BAR domain) reveals a zeppelin-shaped coiled-coil dimer; mutagenesis of conserved basic residues at the dimer tips abrogates F-actin bundling in vitro and filopodia formation in vivo, establishing that IMD-mediated actin bundling is required for filopodia induction. X-ray crystallography, analytical ultracentrifugation, in vitro actin bundling assay, site-directed mutagenesis, filopodia formation assay The EMBO Journal High 15635447
2005 Tiam1 binds IRSp53 and directs it toward Rac (rather than Cdc42) signaling by enhancing IRSp53 binding to active Rac and the WAVE2 scaffold; IRSp53 depletion prevents Tiam1-dependent lamellipodia formation. Co-immunoprecipitation, RNAi knockdown, lamellipodia formation assays, PDGF stimulation Molecular and Cellular Biology Medium 15899863
2006 IRSp53 optimizes WAVE2 complex-mediated Arp2/3 activation in a Rac- and PIP3-dependent manner on membranes; WAVE2 complex isolated from the membrane fraction (but not cytosol) is fully active in an IRSp53-dependent manner. RNAi knockdown, in vitro Arp2/3 activation assay with purified proteins and PIP3-liposomes, membrane fractionation The Journal of Cell Biology High 16702231
2006 Eps8 has intrinsic actin cross-linking activity and synergizes with IRSp53 for actin bundling in vitro; Cdc42 controls the cellular distribution of the IRSp53–Eps8 complex; Cdc42-induced filopodia require both IRSp53 and Eps8. In vitro actin bundling assay, Co-IP, RNAi knockdown, filopodia formation assay Nature Cell Biology High 17115031
2006 The RCB/IMD domain of IRSp53 induces membrane deformation (small buds) on liposomes in a Rac-dependent manner via its convex surface, opposite to the invaginations produced by BAR domains; this activity is independent of actin. Liposome deformation assay, crystal structure of RCB/IMD, mutational mapping of membrane-binding residues, cellular expression of domain constructs The Journal of Biological Chemistry High 17003044
2007 The N-terminal IMD (I-BAR domain) of IRSp53 directly binds PI(4,5)P2-rich membranes and deforms them into tubular structures with curvature opposite to BAR domains (negative curvature/outward protrusion); the membrane-deforming activity of the IMD, rather than its actin-bundling or GTPase-binding activities, is critical for filopodia/microspike induction. In vitro membrane tubulation assay with PI(4,5)P2 liposomes, electron microscopy, mutagenesis, cellular filopodia assay The Journal of Cell Biology High 17371834
2007 Synaptopodin directly binds IRSp53 and suppresses Cdc42:IRSp53:Mena-initiated filopodia formation by blocking the binding of Cdc42 and Mena to IRSp53 in kidney podocytes. Co-immunoprecipitation, pulldown, filopodia formation assay, siRNA knockdown, pharmacological Mena inhibition in vivo The American Journal of Pathology Medium 17569780
2008 IRSp53 directly interacts with N-WASP via its SH3 domain; the I-BAR domain alone induces membrane protrusions lacking actin ('partial filopodia'), while full filopodia require SH3-domain partners (N-WASP and Mena/VASP); Mena/VASP but not N-WASP Arp2/3-activation activity is required for IRSp53-induced filopodia. Co-IP, RNAi knockdown in N-WASP KO and Mena/VASP KO fibroblasts, expression of domain mutants, filopodia reconstitution assay The Journal of Biological Chemistry High 18448434
2008 Par1b directly phosphorylates IRSp53 on S366 (and indirectly on S453/3/5), and a Par1b phosphorylation-deficient IRSp53 mutant rescues cell spreading and lumen polarity defects in Par1b-overexpressing MDCK cells, placing IRSp53 downstream of Par1b in cell-ECM signaling. In vitro kinase assay with cell lysates, site-directed mutagenesis, RNAi knockdown, rescue assays in MDCK cells The Journal of Cell Biology High 21282462
2008 LIN7 recruits IRSp53 to tight junctions via its PDZ domain; loss of LIN7 prevents TJ localization of IRSp53 and reduces Rac1 activation, causing defects in TJ assembly and epithelial cyst polarization. Dominant-negative LIN7 expression, shRNA knockdown, immunofluorescence, Co-IP, Rac1 activation assay Traffic Medium 19054385
2008 Tyrosine 310 in the central unstructured region of IRSp53 is the primary site of phosphorylation downstream of the insulin receptor; the N-terminal IMD domain is required for efficient tyrosine phosphorylation but is not itself phosphorylated. Truncation and point-mutant analysis with insulin/EGF stimulation, Western blotting for phosphotyrosine European Journal of Cell Biology Medium 18417251
2009 IRSp53 family members directly interact with both EHEC Tir (via residues 454–463) and EspFU, colocalizing with EspFU and N-WASP in actin pedestals; loss of IRSp53 abrogates EHEC actin assembly, identifying IRSp53 as the missing host factor linking Tir to EspFU. Co-IP, direct binding assay, genetic loss-of-function (IRSp53 KO cells), immunofluorescence colocalization Cell Host & Microbe High 19286134
2009 IRSp53 knockout mice display a selective increase in NMDA receptor-mediated synaptic transmission (but not AMPA) and markedly enhanced LTP, establishing that IRSp53 negatively regulates NMDA receptor function at excitatory synapses. IRSp53 knockout mice, electrophysiology (AMPA/NMDA ratio, LTP), immunoelectron microscopy of PSD The Journal of Neuroscience High 19193906
2009 Kank specifically inhibits the binding of IRSp53 to active Rac1 (but not Cdc42), thereby suppressing IRSp53-dependent lamellipodia formation without affecting filopodia. Co-IP, direct binding competition assay, RNAi double-knockdown, lamellipodia/filopodia formation assays The Journal of Cell Biology Medium 19171758
2009 14-3-3 binding to phosphorylated residues T340 and T360 (between the CRIB and SH3 domains of IRSp53) inhibits SH3-domain interactions with WAVE2 and Eps8 and blocks Cdc42-GTP binding, extending filopodium lifetimes when these sites are mutated. Phosphorylation mapping, Co-IP, SH3 domain-swapping, live-cell filopodia dynamics imaging Molecular and Cellular Biology High 19933840
2009 Postsynaptic Shank proteins compete with Eps8 for binding to IRSp53, blocking Eps8-IRSp53-dependent actin bundling; IRSp53 KO mice show decreased PSD size and increased NMDA receptor subunits at the PSD. IRSp53 KO mice, competitive binding assay, electrophysiology, LTP measurement The Journal of Biological Chemistry High 19208628
2009 IRSp53 is required for Cdc42-dependent formation of basal filopodia that physically tether presumptive lens and retina to coordinate epithelial invagination during mouse eye development. IRSp53 (Baiap2) conditional KO mice, confocal and electron microscopy, filopodia quantification Development Medium 19820184
2009 SPIN90 directly associates with the SH3 domain of IRSp53 via its proline-rich domain; the SPIN90–IRSp53 complex forms at the leading edge and cooperatively mediates Rac activation and membrane ruffle formation. Co-IP, direct binding assay, siRNA knockdown, competitive inhibition, PDGF stimulation assay Experimental Cell Research Medium 19460367
2010 Tiam1 interacts with both IRSp53 and spinophilin to generate spatially localized Rac activation; IRSp53-dependent Rac activation mediates cell ruffling, spreading, and adhesion, whereas spinophilin-dependent Rac activation mediates cell migration. FRET-based Rac activity assay, RNAi knockdown, cell adhesion/spreading assays, signaling measurements The Journal of Biological Chemistry Medium 20360004
2011 mDia1 and WAVE2 directly interact with IRSp53 within filopodia (confirmed by acceptor-photobleaching FRET); mDia1 and WAVE2 synergize specifically with IRSp53 (not mDia2 or WAVE1) to promote filopodia formation in neuronal cells. FRET (acceptor photobleaching), RNAi knockdown, time-lapse imaging of filopodia formation The Journal of Biological Chemistry High 22179776
2011 The crystal structure of the IRSp53 I-BAR domain in complex with a Tir-derived NPY peptide shows the homodimeric I-BAR binding two parallel Tir molecules; the NPY motif is specifically recognized by a conserved binding site on the I-BAR surface, confirmed by mutagenesis and in vivo binding assays. X-ray crystallography, site-directed mutagenesis, in vivo binding assay Structure High 21893288
2011 IRSp53 depletion reduces Rac1-dependent surface ruffling and CSF-1-induced actin polymerization and cell migration in macrophages; IRSp53 forms an immunoprecipitable complex with WAVE2 and Abi1 in a Rac1-activation-dependent manner, and IRSp53 is required for Rac1 association with WAVE2/Abi1. RNAi knockdown, Co-IP, Rac1Q61L expression, phagocytosis/protrusion assays Journal of Cell Science High 18198193
2012 LIN7 binding to the C-terminal PDZ-binding motif of IRSp53 is required for formation of actin-filled filopodia and neurites in neuronal cells; LIN7 silencing prevents IRSp53 incorporation into Triton X-100-insoluble (membrane-associated) complexes in differentiated cells. LIN7 siRNA knockdown, chimeric protein expression, live-cell imaging, Triton X-100 fractionation, neurite outgrowth assay Journal of Cell Science Medium 22767515
2013 CDC42 switches IRSp53 from inhibiting actin filament barbed-end growth to promoting VASP clustering; IRSp53 inhibits barbed-end growth, which is relieved by CDC42; IRSp53-dependent VASP clustering drives processive actin elongation for filopodia initiation; IRSp53 null mice display defective wound healing. In vitro actin polymerization assays, TIRF microscopy, liposome binding, IRSp53 KO mice wound healing assay, filopodia dynamics imaging The EMBO Journal High 24076653
2013 IRSp53 knockdown attenuates podosome formation and migration in Src-transformed cells; IRSp53 physically interacts with VASP and links small GTPases to VASP for podosome formation; C-terminal splicing isoforms of IRSp53 do not affect this function. RNAi knockdown, Co-IP, podosome formation assay, cell migration assay, deletion mutant expression PLoS One Medium 23555988
2014 Dynamin1 is an IRSp53-interacting partner that localizes to filopodia tips during initiation and assembly; dynamin GTPase activity and its actin-binding domain are required for filopodia formation, placing Dyn1 downstream of IRSp53 in a Dyn1–Mena–Eps8 regulatory network. Pulldown, FRET, RNAi knockdown, pharmacological inhibition (dynasore), TIRF live-cell imaging, expression of GTPase mutants The Journal of Biological Chemistry Medium 25031323
2015 IRSp53 knockout mice display enhanced NMDA receptor function in the hippocampus; treatment with the NMDAR antagonist memantine or the mGluR5 antagonist MPEP normalizes social interaction and NMDAR function/plasticity, establishing a causal link between elevated NMDAR activity and social deficits caused by IRSp53 loss. IRSp53 KO mice, behavioral testing, electrophysiology, pharmacological rescue with memantine/MPEP Nature Neuroscience High 25622145
2015 IRSp53 senses negative membrane curvature via its I-BAR domain; I-BAR dimers display non-monotonic curvature sorting, constricting weakly curved tubes at low tension while expanding them at high tension; at low protein density and tension, protein-rich domains form along membrane tubes. Protein encapsulation in giant unilamellar vesicles connected to membrane nanotubes, theoretical modeling Nature Communications High 26469246
2015 IRSp53 is involved in the Rac1–IRSp53–WAVE2–Arp2/3 signaling pathway; siRNA knockdown of IRSp53 decreases HIV-1 Gag membrane localization and viral particle release in CD4 T cells. siRNA knockdown, immunofluorescence confocal microscopy, membrane flotation assay, immunoblot Journal of Virology Medium 26018170
2019 14-3-3 binds to two pairs of phosphorylation sites in IRSp53; each IRSp53 subunit independently binds one 14-3-3 dimer; 14-3-3 binding causes conformational changes (opposite to activatory Cdc42/Eps8 inputs) and inhibits IRSp53 binding to membranes and to Cdc42/downstream effectors. Phosphoproteomics, quantitative binding assays, crystallography of 14-3-3:phosphopeptide complexes, FRET-sensor assay with bicistronic heterodimer expression Nature Communications High 30696821
2019 AMPK phosphorylates two of the three 14-3-3 binding sites in IRSp53; pharmacological AMPK activation increases IRSp53 phosphorylation and 14-3-3 binding, inhibiting filopodia dynamics and cancer cell chemotaxis; mutating these sites reverses 14-3-3 inhibition. Pharmacological AMPK activation/inhibition, phosphorylation site mutagenesis, live-cell filopodia dynamics imaging, cancer cell chemotaxis assay Molecular Biology of the Cell Medium 30893014
2020 IRSp53 controls lumen formation and positioning of polarity determinants (aPKC, podocalyxin) by regulating RAB35 localization/activity and by interacting with EPS8; IRSp53 genetic removal causes abnormal renal tubulogenesis with altered tubular polarity. IRSp53 KO mouse model, correlative light and electron microscopy (CLEM), Co-IP, RAB35 activity assay Nature Communications High 32665580
2021 IRSp53 I-BAR domain is required for progression of HIV-1 membrane curvature during particle assembly; siRNA knockdown of IRSp53 arrests viral bud at half completion; IRSp53 is found in purified HIV-1 particles and is enriched around Gag assembly sites; HIV-1 Gag localizes preferentially to I-BAR-induced membrane curvature on GUVs. siRNA knockdown, single-molecule localization microscopy, GUV curvature assay, purification of HIV-1 particles with mass spectrometry eLife High 34114563
2022 Full-length IRSp53 self-assembles into clusters on membranes in a PIP2-dependent manner; IRSp53 clusters recruit VASP to locally assemble actin filaments and generate actin-filled membrane protrusions resembling filopodia in vitro; IRSp53 is enriched and triggers actin assembly only at highly dynamic membrane regions in live cells. In vitro reconstitution with GUVs and supported bilayers, live-cell membrane nanotube pulling, TIRF microscopy, molecular dynamics simulation Science Advances High 36240267
2022 Multivalent interactions between IRSp53 and PSD-95 or Shank3 drive liquid-liquid phase separation; IRSp53 is enriched in reconstituted excitatory PSD condensates via bridging to core and deeper PSD layers; PSD condensates promote bundled actin filament formation on membranes via IRSp53-mediated actin binding and bundling; disruption of IRSp53–actin interaction causes synaptic maturation defects in cortical neurons. Phase separation assay (in vitro droplet formation), PSD reconstitution, actin bundling assay on membranes, mutant overexpression in mouse cortical neurons The Journal of Cell Biology High 35819332
2023 Eps8 forms heightened interactions with IRSp53 upon Arp2/3 inhibition, and the Eps8–IRSp53 complex drives linear actin polymerization required for tunnelling nanotube (TNT) formation over long distances. Micropatterning, optical tweezers, proteomics (Eps8 interactome upon Arp2/3 inhibition), RNAi knockdown, time-lapse microscopy The EMBO Journal Medium 38009333
2023 IRSp53 mediates coupling of actin filaments to the plasma membrane at protrusive tips during cell migration on 1D fibers; IRSp53 depletion reduces actin stress fibers originating from cell periphery and uncouples nuclear movement from cell motility; IRSp53 controls retrograde actin flow at cell edges. RNAi knockdown, speckle microscopy for retrograde actin flow, live-cell migration assay on suspended 1D nanofibers, theoretical modeling Advanced Science Medium 36698307
2024 A de novo BAIAP2 variant p.Arg29Trp (in the I-BAR domain) causes a loss-of-function defect by preventing IRSp53 membrane localization; in utero electroporation of Baiap2 knockdown or expression of the variant causes abnormal neuronal migration, morphogenesis, and differentiation in the developing mouse cortex. In utero electroporation (knockdown and variant rescue), spatial transcriptomics, membrane localization assay Development High 38149472
2024 BIN1-mediated filopodia formation requires IRSp53; BIN1 colocalizes with F-actin along filopodia and bundles actin in vitro; BIN1 recruits actin-binding proteins (dynamin, ezrin) to negatively-curved membrane topologies in an IRSp53-dependent manner. RNAi knockdown, in vitro actin bundling assay, Co-IP, immunofluorescence colocalization Communications Biology Medium 38724689
2019 Robo2 binds directly to BAIAP2/IRSp53 through the I-BAR/IMD domain in renal epithelial cells; the Robo2–BAIAP2 complex allows Robo2 to phosphorylate MDM2 at Ser166 via BAIAP2, maintaining p53 homeostasis; disruption of this complex leads to MDM2 dephosphorylation, p53 accumulation, cellular senescence and cystic kidney disease. Co-IP, double KO mouse model, phosphorylation assay, rescue experiments JCI Insight Medium 31534052

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 454 11130076
2001 Cdc42 induces filopodia by promoting the formation of an IRSp53:Mena complex. Current biology : CB 326 11696321
2007 Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. The Journal of cell biology 310 17371834
2006 Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nature cell biology 206 17115031
2008 IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions. Trends in cell biology 203 18215522
2005 Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53. The EMBO journal 198 15635447
2015 IRSp53 senses negative membrane curvature and phase separates along membrane tubules. Nature communications 170 26469246
2006 The RAC binding domain/IRSp53-MIM homology domain of IRSp53 induces RAC-dependent membrane deformation. The Journal of biological chemistry 146 17003044
2007 Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. The American journal of pathology 142 17569780
2015 Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. Nature neuroscience 141 25622145
2006 Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac. The Journal of cell biology 136 16702231
2009 Enhanced NMDA receptor-mediated synaptic transmission, enhanced long-term potentiation, and impaired learning and memory in mice lacking IRSp53. The Journal of neuroscience : the official journal of the Society for Neuroscience 128 19193906
2019 Nanoplasmonic Sensor Detects Preferential Binding of IRSp53 to Negative Membrane Curvature. Frontiers in chemistry 127 30778383
2008 The Cdc42 effector IRSp53 generates filopodia by coupling membrane protrusion with actin dynamics. The Journal of biological chemistry 126 18448434
2009 I-BAR domains, IRSp53 and filopodium formation. Seminars in cell & developmental biology 121 19913105
2003 IRSp53 is colocalised with WAVE2 at the tips of protruding lamellipodia and filopodia independently of Mena. Journal of cell science 113 12734400
2004 IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness. Cancer research 106 15289329
2002 ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. Journal of neurochemistry 100 12421375
2013 CDC42 switches IRSp53 from inhibition of actin growth to elongation by clustering of VASP. The EMBO journal 99 24076653
1995 BAP2, a gene encoding a permease for branched-chain amino acids in Saccharomyces cerevisiae. Biochimica et biophysica acta 96 7495881
2009 IRSp53 links the enterohemorrhagic E. coli effectors Tir and EspFU for actin pedestal formation. Cell host & microbe 89 19286134
2005 Tiam1-IRSp53 complex formation directs specificity of rac-mediated actin cytoskeleton regulation. Molecular and cellular biology 85 15899863
2009 Cdc42- and IRSp53-dependent contractile filopodia tether presumptive lens and retina to coordinate epithelial invagination. Development (Cambridge, England) 81 19820184
2011 mDia1 and WAVE2 proteins interact directly with IRSp53 in filopodia and are involved in filopodium formation. The Journal of biological chemistry 77 22179776
2002 The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42. Molecular and cellular neurosciences 75 12504591
2000 Rho small G-protein-dependent binding of mDia to an Src homology 3 domain-containing IRSp53/BAIAP2. Biochemical and biophysical research communications 73 10814512
1999 Identification of BAIAP2 (BAI-associated protein 2), a novel human homologue of hamster IRSp53, whose SH3 domain interacts with the cytoplasmic domain of BAI1. Cytogenetics and cell genetics 72 10343108
2007 Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties. Journal of cell science 71 17430976
2009 The insulin receptor substrate of 53 kDa (IRSp53) limits hippocampal synaptic plasticity. The Journal of biological chemistry 70 19208628
2008 Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2. Journal of cell science 68 18198193
2015 IRSp53/BAIAP2 in dendritic spine development, NMDA receptor regulation, and psychiatric disorders. Neuropharmacology 64 26275848
1996 Amino acids induce expression of BAP2, a branched-chain amino acid permease gene in Saccharomyces cerevisiae. Journal of bacteriology 64 8606179
2012 Evolution of the eukaryotic ARP2/3 activators of the WASP family: WASP, WAVE, WASH, and WHAMM, and the proposed new family members WAWH and WAML. BMC research notes 53 22316129
2009 Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: association of BAIAP2 with attention-deficit/hyperactivity disorder. Biological psychiatry 53 19733838
2009 Dissecting the role of the Tir:Nck and Tir:IRTKS/IRSp53 signalling pathways in vivo. Molecular microbiology 50 19889090
2001 Transcriptional regulation of the Saccharomyces cerevisiae amino acid permease gene BAP2. Molecular & general genetics : MGG 50 11212916
2011 The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation. PLoS computational biology 49 21814501
2011 The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling. The Journal of cell biology 46 21282462
2009 Regulation of IRSp53-dependent filopodial dynamics by antagonism between 14-3-3 binding and SH3-mediated localization. Molecular and cellular biology 45 19933840
2009 Kank attenuates actin remodeling by preventing interaction between IRSp53 and Rac1. The Journal of cell biology 44 19171758
2019 Mechanism of IRSp53 inhibition by 14-3-3. Nature communications 40 30696821
2022 Activated I-BAR IRSp53 clustering controls the formation of VASP-actin-based membrane protrusions. Science advances 38 36240267
1997 STP1, a gene involved in pre-tRNA processing in yeast, is important for amino-acid uptake and transcription of the permease gene BAP2. Current genetics 37 9065387
2015 Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells. Journal of virology 35 26018170
2023 Tunnelling nanotube formation is driven by Eps8/IRSp53-dependent linear actin polymerization. The EMBO journal 31 38009333
2021 Full assembly of HIV-1 particles requires assistance of the membrane curvature factor IRSp53. eLife 31 34114563
2020 IRSp53 controls plasma membrane shape and polarized transport at the nascent lumen in epithelial tubules. Nature communications 30 32665580
2008 LIN7 mediates the recruitment of IRSp53 to tight junctions. Traffic (Copenhagen, Denmark) 30 19054385
2008 The postsynaptic density protein, IQ-ArfGEF/BRAG1, can interact with IRSp53 through its proline-rich sequence. Brain research 28 19083995
2014 Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons. The Journal of comparative neurology 27 24639075
2010 The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation. Oncogene 26 20418908
2003 MALS is a binding partner of IRSp53 at cell-cell contacts. FEBS letters 26 14596909
2010 Scaffold proteins IRSp53 and spinophilin regulate localized Rac activation by T-lymphocyte invasion and metastasis protein 1 (TIAM1). The Journal of biological chemistry 25 20360004
2001 Distinctive tissue distribution and phosphorylation of IRSp53 isoforms. Biochemical and biophysical research communications 25 11741283
2011 Structural basis for complex formation between human IRSp53 and the translocated intimin receptor Tir of enterohemorrhagic E. coli. Structure (London, England : 1993) 24 21893288
2019 IRSp53 coordinates AMPK and 14-3-3 signaling to regulate filopodia dynamics and directed cell migration. Molecular biology of the cell 22 30893014
2015 SH2B1 and IRSp53 proteins promote the formation of dendrites and dendritic branches. The Journal of biological chemistry 22 25586189
2014 Dynamin1 is a novel target for IRSp53 protein and works with mammalian enabled (Mena) protein and Eps8 to regulate filopodial dynamics. The Journal of biological chemistry 22 25031323
2022 IRSp53 promotes postsynaptic density formation and actin filament bundling. The Journal of cell biology 21 35819332
2012 LIN7 regulates the filopodium- and neurite-promoting activity of IRSp53. Journal of cell science 21 22767515
2015 Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor-dependent signal transduction. Journal of neurochemistry 20 26560964
2023 Actin Filaments Couple the Protrusive Tips to the Nucleus through the I-BAR Domain Protein IRSp53 during the Migration of Cells on 1D Fibers. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 36698307
2004 The N-terminal domain of yeast Bap2 permease is phosphorylated dependently on the Npr1 kinase in response to starvation. FEMS microbiology letters 18 14757244
2017 Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development. Scientific reports 17 28067313
1997 The branched-chain amino acid permease gene of Saccharomyces cerevisiae, BAP2, encodes the high-affinity leucine permease (S1). Yeast (Chichester, England) 17 9153753
2022 Extracellular vesicles containing the I-BAR protein IRSp53 are released from the cell plasma membrane in an Arp2/3 dependent manner. Biology of the cell 16 35844059
2020 IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes. Frontiers in cellular neuroscience 16 32116566
2013 The type III TGFβ receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. The Biochemical journal 16 23750457
2013 IRSp53 mediates podosome formation via VASP in NIH-Src cells. PloS one 15 23555988
2014 BAIAP2 is related to emotional modulation of human memory strength. PloS one 14 24392092
2012 Insulin receptor substrate protein 53kDa (IRSp53) is a negative regulator of myogenic differentiation. The international journal of biochemistry & cell biology 14 22465711
2021 E2F1-Induced lncRNA BAIAP2-AS1 Overexpression Contributes to the Malignant Progression of Hepatocellular Carcinoma via miR-361-3p/SOX4 Axis. Disease markers 13 34616498
2017 Inter-hemispherical asymmetry in default-mode functional connectivity and BAIAP2 gene are associated with anger expression in ADHD adults. Psychiatry research. Neuroimaging 13 28938222
2009 SPIN90-IRSp53 complex participates in Rac-induced membrane ruffling. Experimental cell research 12 19460367
2020 HDAC inhibition induces expression of scaffolding proteins critical for tumor progression in pediatric glioma: focus on EBP50 and IRSp53. Neuro-oncology 11 31711240
2019 Superresolution microscopy reveals distinct localisation of full length IRSp53 and its I-BAR domain protein within filopodia. Scientific reports 11 30792430
2010 The mammalian verprolin, WIRE induces filopodia independent of N-WASP through IRSp53. Experimental cell research 11 20678498
2008 Identification of the insulin-responsive tyrosine phosphorylation sites on IRSp53. European journal of cell biology 11 18417251
2022 Identification of TRAPPC9 and BAIAP2 Gene Polymorphisms and Their Association With Fat Deposition-Related Traits in Hu Sheep. Frontiers in veterinary science 10 35865874
2017 IRSp53 accumulates at the postsynaptic density under excitatory conditions. PloS one 10 29284046
2023 The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice. Molecular psychiatry 8 37730842
2024 A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development. Development (Cambridge, England) 7 38149472
2022 Adult re-expression of IRSp53 rescues NMDA receptor function and social behavior in IRSp53-mutant mice. Communications biology 7 35982261
2022 Suppressed prefrontal neuronal firing variability and impaired social representation in IRSp53-mutant mice. eLife 7 36317872
2014 Ist2 in the yeast cortical endoplasmic reticulum promotes trafficking of the amino acid transporter Bap2 to the plasma membrane. PloS one 7 24416406
2024 BIN1 regulates actin-membrane interactions during IRSp53-dependent filopodia formation. Communications biology 6 38724689
2023 Molecular Relay Stations in Membrane Nanotubes: IRSp53 Involved in Actin-Based Force Generation. International journal of molecular sciences 6 37685917
2014 SH2B1 increases the numbers of IRSp53-induced filopodia. Biochimica et biophysica acta 6 25175559
2010 The neuronal proteins CIPP, Cypin and IRSp53 form a tripartite complex mediated by PDZ and SH3 domains. Biological chemistry 6 20707603
2023 Hippocampal BAIAP2 prevents chronic mild stress-induced depression-like behaviors in mice. Frontiers in psychiatry 5 37234209
2016 Novel localisation and possible function of LIN7 and IRSp53 in mitochondria of HeLa cells. European journal of cell biology 5 27320196
2011 [A molecular dynamics study of the interaction between domain I-BAR of the IRSp53 protein and negatively charged membranes]. Biofizika 5 21542353
2020 IRSp53 is a novel interactor of SHIP2: A role of the actin binding protein Mena in their cellular localization in breast cancer cells. Cellular signalling 4 32535200
2019 Proteomics Analysis Identifies IRSp53 and Fascin as Critical for PRV Egress and Direct Cell-Cell Transmission. Proteomics 4 31531927
2019 Disruption of Robo2-Baiap2 integrated signaling drives cystic disease. JCI insight 4 31534052
2013 Membrane binding properties of IRSp53-missing in metastasis domain (IMD) protein. Biochimica et biophysica acta 3 23872532
2012 LIN7-IRSp53: A novel pathway for filopodia and neurite formation? Communicative & integrative biology 3 23740402
2025 ADAMTS5 Modulates Breast Cancer Development as a Diagnostic Biomarker and Potential Tumour Suppressor, Regulated by BAIAP2-AS1, CRNDE and hsa-miR-135b-3p: Integrated Systems Biology and Experimental Approach. IET systems biology 1 40472834
2023 Negatively curved cellular membranes promote BAIAP2 signaling hub assembly. Nanoscale 1 36943331
2022 Identification of a Rare BAIAP2-ROS1 Fusion and Clinical Benefit of Crizotinib in the Treatment of Advanced Lung Adenocarcinoma: A Case Report. OncoTargets and therapy 1 35923471

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