ITGB1BP1

ITGB1BP1 (ICAP-1) is a PTB-domain phosphoprotein that governs the activation state of β1 integrin and thereby controls cell adhesion, migration, and mechanosensing (PMID:9281591, PMID:9867804). Its PTB domain (residues 58–200) recognizes the NPXY motif of the β1 integrin cytoplasmic tail with strict β1 selectivity, conferred by a hydrophobic pocket (Leu82/Tyr144) that engages Val787 of the integrin (PMID:9281591, PMID:11741908), and this binding suppresses 'inside-out' integrin activation. The cerebral cavernous malformation protein KRIT1 binds the same PTB surface through an N-terminal NPXY-like motif, and co-crystal structures show that KRIT1 directly competes with β1 integrin for ICAP-1, relieving its suppressive effect on integrin activation (PMID:11854171, PMID:23317506, PMID:23695561). ICAP-1 shuttles between cytoplasm and nucleus via a functional NLS, with nuclear localization disabling its integrin-suppressive activity while simultaneously driving KRIT1 into the nucleus; this shuttling is controlled by PAK4-mediated Ser-10 phosphorylation, which restrains nuclear accumulation, and by Smurf1-mediated monoubiquitylation, which blocks β1 binding (PMID:28003363, PMID:28049720, PMID:32005669). Beyond integrin binding, ICAP-1 acts as a guanine nucleotide dissociation inhibitor for Cdc42 and Rac1 and recruits ROCK-I to β1 integrin adhesion sites, integrating these activities into mechanotransduction—including a Smurf1-controlled switch between ROCK2- and MRCKα-dependent contractility and isoform-specific (ICAP-1α) tuning of talin tension on stiff matrices (PMID:11807099, PMID:16741948, PMID:17654484, PMID:28049720, PMID:41617095). In vivo, ICAP-1 loss in mice disrupts CD8+ single-positive thymocyte generation and dysregulates β4β1-mediated lymphocyte adhesion (PMID:35491946).

1. 1997 High

   Established the founding molecular interaction—that ICAP-1 specifically engages the β1 integrin cytoplasmic tail via its NPXY motif and is regulated by adhesion-dependent phosphorylation—defining ICAP-1 as an integrin-tail-binding adaptor.

   Evidence Yeast two-hybrid, NPXY mutagenesis, and adhesion/phosphorylation assays on fibronectin

   PMID:9281591

   Open questions at the time

   • Functional consequence of the interaction for integrin activation not yet defined
   • Kinase responsible for ICAP-1 phosphorylation unidentified
2. 1999 High

   Demonstrated that the ICAP-1/β1 interaction is functionally consequential, linking it to β1-dependent chemotactic migration and confirming binding specificity for β1 over other β subunits.

   Evidence Yeast two-hybrid, co-IP in human cells, and migration assays with wild-type/mutant β1 in CHO cells

   PMID:9867804

   Open questions at the time

   • Whether ICAP-1 activates or suppresses integrin not resolved
   • Downstream effectors of migration phenotype unknown
3. 2001 High

   Mapped the binding interface to the PTB domain at residue resolution, explaining the structural basis of β1 specificity through identified contact residues on both partners.

   Evidence Alanine-scanning and site-directed mutagenesis guided by PTB homology modeling

   PMID:11741908

   Open questions at the time

   • Lacked a crystal structure to confirm the modeled interface
   • Regulation of the interface in cells unaddressed
4. 2002 High

   Identified KRIT1 as a second NPXY-motif partner of ICAP-1, foreshadowing a competition between two distinct ligands for the same adaptor.

   Evidence Yeast two-hybrid screen and GST-KRIT1 pulldown of endogenous ICAP-1, with NPXY mutagenesis

   PMID:11854171

   Open questions at the time

   • Whether KRIT1 and β1 bind the same ICAP-1 surface not yet shown
   • Functional outcome of KRIT1 binding undefined
5. 2002 High

   Revealed an integrin-independent activity, showing ICAP-1 functions as a GDI for Cdc42/Rac1 to restrain cell spreading, broadening its role into Rho-family GTPase regulation.

   Evidence In vitro binding and GDP-dissociation assays, GTPase activation assays, membrane fractionation, and epistasis with constitutively active Cdc42

   PMID:11807099

   Open questions at the time

   • Integration of GDI activity with integrin-tail binding unclear
   • In vivo relevance of GDI function not tested
6. 2006 High

   Connected ICAP-1 to actomyosin regulation by showing it binds and translocates ROCK-I to the plasma membrane independently of integrin ligation or kinase activity.

   Evidence Yeast two-hybrid, reciprocal co-IP, FRET between CFP-ICAP-1 and YFP-ROCK, and truncation mapping

   PMID:16741948

   Open questions at the time

   • Functional consequence of ROCK translocation not yet shown
   • Relationship to GDI and integrin functions unresolved
7. 2008 Medium

   Linked ROCK translocation to physiology, showing ICAP-1 regulates β1-dependent migration and focal adhesion organization through ROCK recruitment to adhesion sites.

   Evidence RNAi, overexpression, migration and focal-adhesion assays, and pharmacological ROCK inhibition (Y-27632) in myoblasts and endothelial cells

   PMID:17654484

   Open questions at the time

   • Single lab
   • Direct molecular link between ICAP-1 and adhesion-site ROCK localization not structurally defined
8. 2013 High

   Resolved the central mechanistic question by crystallography, proving that KRIT1 competes with β1 integrin for the same ICAP-1 PTB surface to antagonize ICAP-1-mediated suppression of integrin activation.

   Evidence Co-crystal structures of KRIT1–ICAP1 and ICAP1–β1 tail (and a 1.7 Å ICAP1–KRIT1 peptide structure), with integrin activation and competitive binding assays

   PMID:23317506 PMID:23695561

   Open questions at the time

   • How the competition is regulated dynamically in cells not addressed
   • Spatial coordination of the two ligand pools unknown
9. 2016 Medium

   Established nuclear-cytoplasmic shuttling as a regulatory layer, showing ICAP-1 has an NLS whose use both disables integrin suppression and drives KRIT1 into the nucleus.

   Evidence NLS mutagenesis with integrin activation flow cytometry and fluorescence microscopy

   PMID:28003363

   Open questions at the time

   • Signals triggering shuttling not identified here
   • Nuclear function of ICAP-1/KRIT1 undefined
10. 2017 Medium

    Identified monoubiquitylation as a switch, showing Smurf1 modifies ICAP-1 to block β1 binding and toggle contractility from ROCK2- to MRCKα-dependent, coupling ICAP-1 to rigidity sensing.

    Evidence Ubiquitylation assays with Smurf1, non-ubiquitylatable mutant rescue, focal-adhesion and myosin-phosphorylation assays, migration on varying density/stiffness substrates

    PMID:28049720

    Open questions at the time

    • Single lab
    • Ubiquitylation site(s) and deubiquitylase not defined
11. 2020 High

    Defined the kinase input controlling shuttling, showing PAK4 phosphorylates ICAP-1 at Ser-10 to inhibit nuclear accumulation of the ICAP1–KRIT1 complex.

    Evidence Phosphomimetic/blocking mutagenesis, quantitative microscopy, and in vitro plus cell-based PAK4 kinase assays

    PMID:32005669

    Open questions at the time

    • Upstream signals activating PAK4 toward ICAP-1 unknown
    • Phosphatase reversing Ser-10 unidentified
12. 2022 Medium

    Provided in vivo physiological context, showing ICAP-1 loss disrupts CD8+ thymocyte generation and dysregulates β4β1-mediated lymphocyte adhesion, with strong nuclear ICAP-1 in thymocytes.

    Evidence ICAP-1 knockout mice with flow cytometry, nuclear/cytoplasmic fractionation, and adhesion/proliferation assays

    PMID:35491946

    Open questions at the time

    • No direct mechanistic link between nuclear ICAP-1 and Runx3 established
    • Single lab
13. 2024 Low

    Extended ICAP-1 function beyond β1 integrins, implicating it in LFA-1 (β2 integrin)-directed T cell polarity and transmigration.

    Evidence RNAi knockdown in primary human T cells with polarity and transmigration assays toward SDF-1

    PMID:39607284

    Open questions at the time

    • No molecular mechanism established for the β2 integrin connection
    • Single lab, knockdown only
14. 2026 Medium

    Cast ICAP-1 as an isoform-specific mechanotransducer, showing ICAP-1α (not β) reduces cancer cell aggressiveness and dampens talin tension on stiffness gradients.

    Evidence Isoform-specific expression, cell-derived matrix migration assays, FRET talin tension sensor, and integrin activity assays in NSCLC cells

    PMID:41617095

    Open questions at the time

    • Single lab, not replicated
    • Mechanism by which stiffness shifts isoform expression undefined

• How the multiple regulatory inputs—phosphorylation, monoubiquitylation, nuclear shuttling, and isoform switching—are integrated in real time at adhesion sites, and what ICAP-1/KRIT1 does in the nucleus, remain open.
• Nuclear function of the ICAP-1/KRIT1 complex uncharacterized
• Quantitative hierarchy of competing regulatory modifications not established
• Mechanism coupling β2 integrin function to known β1/KRIT1 biology unknown