Affinage

ITGA4

Integrin alpha-4 · UniProt P13612

Length
1032 aa
Mass
114.9 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITGA4 encodes the α4 integrin subunit (CD49d) that heterodimerizes with β1 (CD29) to form VLA-4, a leukocyte adhesion receptor that engages VCAM-1 and the CS-1/fibronectin sequence to control cell trafficking, survival, and signaling (PMID:7531439, PMID:16943205). Ligand engagement is conferred by α4 residues 108–268 outside the cation-binding motifs, with the partnering β1 Asp-130 being critical for binding both VCAM-1 and CS-1 (PMID:7531439). VLA-4 ligation transduces intracellular signals, triggering phosphoinositide turnover and biphasic Ca²⁺ mobilization (PMID:9209507), and when co-engaged with the TCR it costimulates NF-AT, AP-1, and NF-κB activation and cytokine secretion in T cells (PMID:8757316). Functionally, VLA-4–mediated adhesion to VCAM-1 or fibronectin protects germinal-center and serum-deprived B cells from apoptosis (PMID:7511659, PMID:11966761), augments eosinophil degranulation (PMID:8049081), and drives neutrophil release from bone marrow and dendritic-cell transendothelial migration (PMID:15542579, PMID:11035069). The receptor operates within larger membrane assemblies: it associates with tetraspanins CD81, CD82, CD63, and CD53 (PMID:8757325), forms constitutive complexes with CD38 (PMID:22289918) and with CD44 — the latter creating ligand-induced proximity that gives both receptors access to FAK, lck, src, paxillin, and MAPK to amplify adhesion, migration, and apoptosis resistance (PMID:17039568, PMID:24127558). VLA-4 affinity is dynamically controlled by inside-out activation downstream of BCR triggering through a PI3K-dependent pathway (PMID:29301866). ITGA4 expression is governed at multiple levels: transcriptionally by RUNX3, FEV, and NOTCH1/NF-κB (PMID:16164020, PMID:35875066, PMID:28935990), epigenetically by promoter methylation (PMID:24068493), and post-transcriptionally by METTL3-mediated m6A stabilization of its mRNA (PMID:36266324). These regulatory inputs drive ITGA4 function in malignancy, where it promotes AML and CLL homing and survival (PMID:36266324, PMID:35875066) and, via a CAF-derived laminin α5–ITGA4–STAT3 axis, drives acinar-to-ductal metaplasia in pancreatic cancer initiation (PMID:38154529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Defining which α4 regions mediate ligand recognition established the structural basis for VLA-4 engagement of VCAM-1 and fibronectin.

    Evidence Interspecies α4 chimeras, function-blocking mAb epitope mapping, and a β1 D130A dominant-negative mutant in CHO adhesion assays

    PMID:7531439

    Open questions at the time
    • No atomic-resolution structure of the α4/β1 ligand interface
    • Does not address affinity regulation or inside-out activation
  2. 1994 Medium

    Showing that VLA-4 adhesion to VCAM-1/fibronectin prevents B-cell apoptosis established the receptor as a pro-survival, not merely structural, signal.

    Evidence Blocking-mAb disruption of FDC-B cell clusters and adhesion to purified VCAM-1 with apoptosis readout in tonsil B cells; later confirmed with fibronectin fragments

    PMID:11966761 PMID:7511659

    Open questions at the time
    • Survival signaling pathway downstream of α4 not defined
    • Protection is pathway-specific (no rescue from Fas or IgM apoptosis)
  3. 1996 Medium

    Identifying VLA-4 as a signaling receptor that mobilizes Ca²⁺/IP3 and costimulates T-cell transcription factors moved it beyond passive adhesion to active immune signaling.

    Evidence Fura-2 Ca²⁺ imaging and IP3 assays in Jurkat cells; EMSA and cytokine ELISA with co-immobilized VCAM-1 plus anti-CD3 in primary T cells

    PMID:8757316 PMID:9209507

    Open questions at the time
    • Proximal kinases linking α4 to phosphoinositide signaling not identified
    • Single-lab observations
  4. 1996 High

    Demonstrating physical association of VLA-4 with tetraspanins placed the integrin within a membrane microdomain network.

    Evidence Reciprocal Co-IP and confocal colocalization with CD81/CD82/CD63/CD53; adhesion-deficient α4 mutants (D346E, D408E) lose CD81 association

    PMID:8757325

    Open questions at the time
    • Functional consequence of tetraspanin association not fully resolved
    • Stoichiometry of the complex unknown
  5. 2004 High

    Establishing that CD49d is required for chemokine-driven neutrophil release from bone marrow assigned VLA-4 a distinct trafficking role opposite to CD18.

    Evidence In situ rat femoral bone marrow perfusion with neutralizing mAb and small-molecule CD49d antagonist versus CD18 blockade

    PMID:15542579

    Open questions at the time
    • Molecular trigger switching VLA-4 from retention to release not defined
    • Rat model; human extrapolation untested here
  6. 2006 High

    Mapping VLA-4 to VCAM-1 modules 1–3 versus αMβ2 to module 4 resolved how distinct integrins partition a shared ligand under activation states.

    Evidence Antibody-blocking and PI3K-inhibitor adhesion assays with VCAM-1 deletion constructs under flow and static conditions

    PMID:16943205

    Open questions at the time
    • Does not address VLA-4 affinity modulation by IL-5
    • Confined to eosinophil systems
  7. 2006 High

    Discovering ligand-induced CD44–CD49d proximity that cross-licenses FAK and lck explained how adhesion receptors cooperatively amplify motility and survival.

    Evidence In vivo Co-IP from lymph node cells plus blocking and kinase-readout assays; later confirmed by reciprocal cytoplasmic-tail point mutants in leukemia cells in vitro and in vivo

    PMID:17039568 PMID:24127558

    Open questions at the time
    • Structural basis of the CD44–CD49d contact unresolved
    • Whether the complex forms in non-malignant settings broadly untested
  8. 2003 Medium

    Gain-of-function showed CD49d overexpression alone confers antigen-independent autoreactivity and enhanced homing, defining its capacity to lower activation thresholds.

    Evidence CD49d cDNA transfection in D10 T cells with antigen-independent proliferation, endothelial adhesion, and in vivo splenic homing assays

    PMID:12847241

    Open questions at the time
    • Does not induce cytotoxicity or overt autoimmunity, so downstream limits are unclear
    • Single-lab gain-of-function
  9. 2012 High

    Defining a constitutive CD49d–CD38 complex that boosts adhesion and Vav-1 signaling identified a co-receptor that intensifies VLA-4 output in CLL.

    Evidence Cocapping, Co-IP, CD38 transfection rescue, phospho-Vav-1 blots, F-actin and apoptosis assays in primary CLL cells

    PMID:22289918

    Open questions at the time
    • Whether the CD49d–CD38 complex operates in normal lymphocytes not established
  10. 2018 High

    Linking BCR-driven inside-out VLA-4 activation to a BTK-independent, PI3K-dependent pathway clarified how integrin affinity is set in CLL and modulated by ibrutinib.

    Evidence VLA-4 activation/adhesion assays with in vitro and in vivo ibrutinib, BCR stimulation, and PI3K-inhibitor rescue in CLL cells

    PMID:29301866

    Open questions at the time
    • Molecular adaptors executing inside-out activation downstream of PI3K not identified
  11. 2017 High

    Identifying multiple transcriptional and epigenetic controls explained how ITGA4 surface levels are tuned across cell states and tumors.

    Evidence RUNX3 and FEV promoter transactivation, NOTCH1-ICD/NF-κB induction, and 5-aza-dC demethylation rescue with bisulfite sequencing across DC, AML, and CLL systems

    PMID:16164020 PMID:24068493 PMID:28935990 PMID:35875066

    Open questions at the time
    • Hierarchy and crosstalk among these regulators not integrated
    • Most assays single-lab and context-specific
  12. 2022 High

    Showing METTL3-mediated m6A stabilizes ITGA4 mRNA added a post-transcriptional layer controlling integrin abundance and leukemic homing.

    Evidence mRNA half-life measurement, METTL3 knockdown/overexpression and inhibitor, with in vivo AML homing/engraftment

    PMID:36266324

    Open questions at the time
    • m6A reader directing ITGA4 mRNA stabilization not identified
    • Specific methylated sites not mapped
  13. 2023 High

    Defining a CAF-laminin α5–ITGA4–STAT3 axis driving acinar-to-ductal metaplasia extended ITGA4 function to epithelial tumor initiation beyond leukocytes.

    Evidence Integrated proteomics/transcriptomics with genetic depletion validated in cell lines, organoids, explants, and mouse coculture models

    PMID:38154529

    Open questions at the time
    • How ITGA4 engagement couples to STAT3 activation mechanistically unresolved
  14. 2025 High

    CRISPR deletion of CD49d in CAR-T cells reduced off-tumor toxicity while preserving efficacy, establishing ITGA4 as a manipulable mediator of T-cell tissue infiltration.

    Evidence CRISPR KO of CD11a/CD49d (and PSGL1) in CAR-T cells with in vivo toxicity, efficacy, memory phenotyping, and tonic-signaling readouts

    PMID:39841806

    Open questions at the time
    • Which tissues depend on CD49d for CAR-T entry not delineated
    • Link between CD49d loss and reduced tonic signaling mechanistically unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural and signaling model linking VLA-4 affinity states, its co-receptor complexes (tetraspanins, CD38, CD44), and the specific kinase cascades that translate adhesion into survival and transcriptional output remains unresolved.
  • No high-resolution structure of α4β1 with ligand or partner receptors
  • Proximal signaling adaptors connecting α4 to phosphoinositide and STAT3 pathways unidentified
  • m6A reader and inside-out adaptor proteins unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
ADAM2CD38CD44CD81ITGB1LAMA5VCAM1
Complex memberships
VLA-4 (α4β1)α4β7

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Ligand-binding sites of integrin α4 (CD49d/ITGA4) were mapped using interspecies chimeras: residues 108–268 (not including bivalent-cation-binding motifs) are involved in VCAM-1 and CS-1/fibronectin binding, with epitopes B1 (residues 195–268) and B2 (residues 108–182) specifically associated with ligand binding. The β1 subunit Asp-130 was shown to be critical for binding both VCAM-1 and CS-1 peptide via a dominant-negative D130A mutant. Interspecies α4 chimeras expressed in mammalian cells; epitope mapping with function-blocking mAbs; CHO cell adhesion assay with β1 D130A mutant The Biochemical journal High 7531439
1996 Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associate with α4β1 (CD49d/CD29) as shown by reciprocal co-immunoprecipitation and colocalization by confocal microscopy. The association is independent of divalent cations, integrin-activating mAb, or α4 cytoplasmic domain, but two α4 adhesion-deficient mutants (D346E, D408E) lack CD81 association, suggesting the interaction is functionally relevant. Reciprocal co-immunoprecipitation; confocal microscopy colocalization; adhesion-deficient α4 mutant cell lines Journal of immunology High 8757325
1996 Ligation of VLA-4 (α4β1/CD49d) on Jurkat T cells with cross-linked anti-α4 mAb triggers a biphasic Ca²⁺ response and stimulates production of myo-inositol 1,4,5-trisphosphate, demonstrating that CD49d engagement activates the phosphoinositide signaling pathway and Ca²⁺ mobilization. Fluorometric Ca²⁺ measurement (Fura-2); inositol trisphosphate production assay; confocal microscopy; antibody blocking of VLA-4/VCAM-1 interaction European journal of immunology Medium 9209507
1996 Co-immobilized VCAM-1 (VLA-4/CD49d ligand) with anti-CD3 mAb significantly enhanced induction of transcription factors NF-AT, AP-1, and NF-κB (by EMSA) and cytokine secretion (IL-2, TNF-α, IFN-γ, GM-CSF) in freshly isolated T cells. The costimulatory effect did not lower the anti-CD3 dose-response threshold, indicating α4β1 delivers a distinct signal that synergizes with TCR/CD3 signaling. Electromobility shift assay (EMSA) for transcription factor binding; cytokine ELISA; co-immobilized ligand stimulation assay Journal of immunology Medium 8757316
1994 VLA-4 (CD49d/CD29)-mediated adhesion to FDC via VCAM-1 prevents apoptosis of germinal center B cells; disruption of this adhesion with anti-CD49d, anti-VCAM-1, anti-CD11a, or anti-ICAM-1 mAbs results in B cell apoptosis. Adhesion of GC B cells to plastic-coated VCAM-1 alone diminishes apoptosis, and at low concentrations VCAM-1 acts synergistically with anti-IgM to inhibit apoptosis. Disruption of FDC-B-cell clusters with blocking mAbs; adhesion to purified VCAM-1- or ICAM-1-coated surfaces; apoptosis assay in human tonsil-derived cells Journal of immunology Medium 7511659
1994 VLA-4 (CD49d)-mediated adhesion of eosinophils to fibronectin augments stimulated eosinophil peroxidase (EPO) degranulation in response to FMLP+cytochalasin B; this augmentation was specifically blocked by the anti-VLA-4 mAb HP2/1, which also reduced eosinophil adhesion to fibronectin. EPO release assay; adhesion assay to fibronectin-coated plates; function-blocking anti-VLA-4 mAb (HP2/1) American journal of respiratory cell and molecular biology Medium 8049081
2000 CD49d integrin expression is induced/up-regulated during TNF-α- or LPS-initiated maturation of monocyte-derived dendritic cells (MDDC), dependent on NF-κB activation (blocked by N-acetylcysteine) and p38 MAPK (blocked by SB203580). Up-regulated CD49d confers mature MDDC with elevated capacity to adhere to the CS-1 fibronectin fragment and mediates transendothelial migration. Flow cytometry; Northern blot for CD49d mRNA; transendothelial migration assay; pharmacological inhibitors of NF-κB and p38 MAPK Journal of immunology Medium 11035069
2005 The transcription factor RUNX3 transactivates the CD49d (ITGA4) gene promoter; overexpression of RUNX3 in monocyte-derived dendritic cells correlates with up-regulation of CD49d mRNA and CD49d integrin surface expression, establishing RUNX3 as a transcriptional regulator of ITGA4. CD49d gene promoter reporter/transactivation assay; RUNX3 overexpression; RT-PCR for CD49d mRNA; flow cytometry for CD49d protein Immunobiology Medium 16164020
2006 α4β1 (CD49d/CD29) mediates eosinophil adhesion to VCAM-1 modules 1–3 (6d-VCAM-1), while module 4 of VCAM-1 is additionally engaged by αMβ2. PI3K inhibitors block αMβ2-mediated adhesion to module 4 but not α4β1-mediated adhesion to modules 1–3. IL-5 activation switches eosinophil adhesion to 7d-VCAM-1 to be predominantly αMβ2-dependent. Antibody blocking adhesion assays; PI3K inhibitors; eosinophilic cell lines lacking αMβ2; static and flow adhesion assays with VCAM-1 deletion constructs The Journal of biological chemistry High 16943205
2004 CD49d (α4-integrin) is required for MIP-2-stimulated neutrophil mobilization from rat bone marrow: blockade of CD49d with neutralizing mAb or a specific antagonist inhibited chemokine-stimulated neutrophil release by >75%. In contrast, CD18 blockade did not inhibit but instead increased neutrophil mobilization, indicating contrasting roles for CD18 (retention) and CD49d (release). In situ rat femoral bone marrow perfusion system; neutralizing mAbs and small molecule antagonist for CD49d; flow cytometry for integrin surface levels Blood High 15542579
2012 CD49d/CD29 (α4β1) integrin and CD38 form a constitutive physical complex in primary CLL cells, demonstrated by cocapping, co-immunoprecipitation, and functional adhesion experiments. CD38 co-expression enhances CD49d-mediated cell adhesion to VCAM-1 and CS-1/fibronectin substrates, triggers higher phospho-Vav-1 levels, and increases F-actin redistribution at adhesion sites and apoptosis resistance. Cocapping; co-immunoprecipitation; CD49d-specific substrate adhesion assay; CD38 transfection in CD38-negative CLL cell line; phospho-Vav-1 Western blot; F-actin staining; apoptosis assay Leukemia High 22289918
2017 NOTCH1 pathway activation drives CD49d (ITGA4) expression in CLL cells via NF-κB: stable expression of the NOTCH1 intracellular domain in MEC-1 cells up-regulates CD49d, and pharmacological inhibition of NOTCH1 or NF-κB reduces NF-κB nuclear translocation and down-modulates CD49d expression. Stable NOTCH1-ICD transfection in MEC-1 cells; NOTCH1/NF-κB pathway inhibitors; NF-κB nuclear translocation assay; flow cytometry for CD49d Leukemia Medium 28935990
2018 VLA-4 integrin (CD49d) undergoes inside-out activation upon BCR triggering in CD49d-positive CLL cells, reinforcing cell adhesion. In vitro and in vivo ibrutinib treatment reduces constitutive VLA-4 activation and adhesion, but this can be overcome by exogenous BCR stimulation via a BTK-independent, PI3K-dependent mechanism. VLA-4 activation assay; adhesion assay; ibrutinib treatment in vitro and in vivo; BCR stimulation; PI3K inhibitor rescue experiments The Journal of experimental medicine High 29301866
2022 METTL3-mediated m6A methylation stabilizes ITGA4 mRNA by extending its half-life, increasing ITGA4 protein expression and thereby enhancing AML cell homing and engraftment in bone marrow. A METTL3 inhibitor reversed these effects. RNA sequencing; reverse-phase protein arrays; mRNA half-life measurement; METTL3 knockdown/overexpression; METTL3 inhibitor treatment; in vivo homing/engraftment assay Leukemia High 36266324
2022 The transcription factor FEV directly activates ITGA4 transcription in a dose-dependent manner, promoting AML cell homing and expansion. Inhibition of integrin α4 with natalizumab reduced migration and colony-forming abilities of AML blasts and leukemic-initiating cells. FEV overexpression/knockdown in AML cell lines; ITGA4 promoter transcription activation assay; natalizumab functional blocking; migration and colony-forming assay Frontiers in oncology Medium 35875066
2023 CAF-secreted laminin α5 (LAMA5) engages ITGA4 on acinar cells to activate STAT3 signaling, driving acinar-to-ductal metaplasia (ADM) in pancreatic cancer initiation. Depletion of LAMA5/ITGA4/STAT3 axis components blocked CAF-induced ADM in cell lines, organoids, explants, and mouse models. Proteomic/transcriptomic data integration (LC-MS/MS + RNA-seq); confocal microscopy; immunoblotting; qRT-PCR; ITGA4/LAMA5 depletion in cell line, acinar explant coculture, and mouse CAF coculture models Gastroenterology High 38154529
2006 CD44 and CD49d form a physical complex in activated lymphocytes in vivo in autoimmune disease (murine alopecia areata model); this association allows CD44 to access FAK and CD49d to access lck and ezrin, such that ligand binding of either molecule activates downstream kinases of both, enhancing lymphocyte motility, proliferation, and apoptosis resistance. Co-immunoprecipitation from in vivo lymph node cells; functional blocking of CD44 and CD49d; proliferation, migration, and apoptosis assays; kinase activation readouts European journal of immunology Medium 17039568
2013 CD44 and CD49d cooperate in leukemia cell adhesion, migration, and apoptosis resistance via ligand-induced proximity giving both access to src, FAK, paxillin, and lck/MAPK pathways; cooperation was abrogated by point mutations in CD49d that prevent FAK binding or in CD44 that prevent ezrin binding, establishing that physical contact and cytoplasmic tail integrity are required. CD49d transfection (wild-type and phosphorylation/FAK-binding mutant); CD44 transfection (wild-type and ezrin-binding/tail-truncated mutant); adhesion, migration, and apoptosis assays in vitro and in vivo; ligand-binding and antibody-blocking studies Journal of immunology High 24127558
2003 CD49d overexpression in murine T cells (by transfection) is sufficient to induce autoreactivity (MHC class II-dependent proliferation to APCs without antigen) and increases adhesion to endothelial cells and in vivo splenic homing. However, unlike LFA-1 overexpression, CD49d overexpression does not induce cytotoxicity or in vivo autoimmunity. CD49d cDNA transfection into D10 T cells; antigen-independent proliferation assay; adhesion assay to endothelial cells; in vivo splenic homing assay; cytotoxicity assay Journal of immunology Medium 12847241
2013 CD49d promoter methylation inversely correlates with CD49d expression in CLL; trisomy 12 CLL cells show near-complete demethylation and highest CD49d expression. Treatment of hypermethylated CD49d-negative CLL cells with the hypomethylating agent 5-aza-2'-deoxycytidine restores CD49d expression, demonstrating methylation-dependent transcriptional silencing. Bisulfite genomic sequencing; flow cytometry for CD49d protein; 5-aza-2'-deoxycytidine demethylation assay; correlation analysis in cohort of 1200 CLL cases Blood High 24068493
2019 CD49d/CD29 (α4β1) integrin is required for recruitment of plasmacytoid dendritic cells (pDCs) into the CNS during EAE; adoptive transfer experiments showed pDCs accumulate in brain and spinal cord, and this accumulation was strongly inhibited when CD29 (β1) was absent or when CD49d was blocked, whereas CD18 blockade had no effect. Adoptive transfer of pDCs; CD49d blocking antibody treatment during EAE; CD29-deficient mice; enumeration of CNS-pDCs by flow cytometry European journal of immunology Medium 31318439
2002 CD49d on human NK cells interacts with porcine VCAM-1 (CD106) to mediate rolling adhesion (>75% reduction upon blocking either partner) and contributes to firm static adhesion (~60% reduction); simultaneous blockade of CD49d and CD11a abolished ~82% of static adhesion, establishing CD49d-VCAM-1 as the dominant rolling adhesion pathway for NK cells on porcine endothelium. Shear stress flow adhesion assay; static adhesion assay; blocking mAbs to CD49d, CD106, and other adhesion molecules; NK92 cell line (FcγRIII-negative control) Transplantation Medium 11907429
2002 α4β1 (CD49d/CD29) engagement by fibronectin fragment H89 (but not FN-III4-5 activated-form fragment) protects B cells from serum deprivation-induced apoptosis; this protection is specifically reversed by anti-α4 mAb. However, α4 engagement does not protect against IgM-triggered or Fas/APO-1-mediated apoptosis, demonstrating pathway specificity. B cell adhesion to recombinant fibronectin fragments; viability/apoptosis assay; anti-α4 mAb blocking; Fas-triggering and anti-IgM apoptosis assays Clinical and experimental immunology Medium 11966761
2010 ITGA4 (CD49d) on mouse eggs interacts with ADAM2 via an integrin β1-dependent mechanism; anti-β1 function-blocking antibody significantly inhibits ADAM2 binding to eggs. Additionally, ITGA9-ITGB7 (a novel α-β combination identified in RPMI 8866 cells lacking ITGB1) functions as an ADAM2 binding partner, revealed by antibody and siRNA studies. Anti-β1 function-blocking antibody adhesion assay; siRNA knockdown of ITGB7; anti-ITGA9 antibody blocking; adhesion assay to ADAM2 PloS one Medium 21060781
2025 Knockout of both CD11a and CD49d (or triple knockdown with PSGL1) in CAR-T cells reduces on-target/off-tumor toxicity in vivo without impairing anti-tumor efficacy; the modification also promotes T cell memory formation and decreases tonic signaling, establishing CD49d as a mediator of CAR-T tissue infiltration and toxicity. CRISPR knockout of CD11a and CD49d in CAR-T cells; in vivo mouse toxicity and efficacy assays; T cell memory phenotyping; tonic signaling measurement Science translational medicine High 39841806

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)-VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. Journal of immunology (Baltimore, Md. : 1950) 274 7511659
1996 Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). Journal of immunology (Baltimore, Md. : 1950) 200 8757325
2015 Identification and characterization of VEGF-A-responsive neutrophils expressing CD49d, VEGFR1, and CXCR4 in mice and humans. Blood 198 26286848
2009 Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood 166 19228923
2009 CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer research 138 19383907
1997 Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. The Journal of clinical investigation 126 9399955
1995 Identification of putative ligand-binding sites of the integrin alpha 4 beta 1 (VLA-4, CD49d/CD29). The Biochemical journal 119 7531439
2008 Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke 118 18309158
2010 CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. Journal of immunology (Baltimore, Md. : 1950) 93 20525890
2018 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. The Journal of experimental medicine 84 29301866
1996 L- and P-selectins, but not CD49d (VLA-4) integrins, mediate monocyte initial attachment to TNF-alpha-activated vascular endothelium under flow in vitro. Journal of immunology (Baltimore, Md. : 1950) 84 8683134
2004 The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner. Blood 83 15542579
2022 METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4. Leukemia 81 36266324
2012 The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells. Leukemia 77 22289918
2001 The alpha 4 beta 1 (very late antigen (VLA)-4, CD49d/CD29) and alpha 5 beta 1 (VLA-5, CD49e/CD29) integrins mediate beta 2 (CD11/CD18) integrin-independent neutrophil recruitment to endotoxin-induced lung inflammation. Journal of immunology (Baltimore, Md. : 1950) 68 11254723
2000 Maturation-dependent expression and function of the CD49d integrin on monocyte-derived human dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 67 11035069
2008 CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia. Haematologica 62 18641015
1994 Augmentation of stimulated eosinophil degranulation by VLA-4 (CD49d)-mediated adhesion to fibronectin. American journal of respiratory cell and molecular biology 59 8049081
2012 Evaluating the performance of fibronectin 1 (FN1), integrin α4β1 (ITGA4), syndecan-2 (SDC2), and glycoprotein CD44 as the potential biomarkers of oral squamous cell carcinoma (OSCC). Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 58 23116545
2000 VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis. Journal of neuroimmunology 56 11063837
2010 Detection of colorectal neoplasm using promoter methylation of ITGA4, SFRP2, and p16 in stool samples: a preliminary report in Korean patients. Hepato-gastroenterology 55 21033217
1997 Therapy with antibody against leukocyte integrin VLA-4 (CD49d) is effective and safe in virus-facilitated experimental allergic encephalomyelitis. Journal of neuroimmunology 54 9003249
2010 Cutting edge: CD49d+ neutrophils induce FcepsilonRI expression on lung dendritic cells in a mouse model of postviral asthma. Journal of immunology (Baltimore, Md. : 1950) 52 20876348
2020 CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood 50 32006000
2013 CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism. Blood 50 24068493
1996 Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered sensitivity to anti-CD3 stimulation. Journal of immunology (Baltimore, Md. : 1950) 50 8757316
2015 Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. Journal of cancer research and clinical oncology 47 25902909
2010 CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function. Bone marrow transplantation 47 20098455
1995 IL-1 activation of endothelium supports VLA-4 (CD49d/CD29)-mediated monocyte transendothelial migration to C5a, MIP-1 alpha, RANTES, and PAF but inhibits migration to MCP-1: a regulatory role for endothelium-derived MCP-1. Journal of leukocyte biology 47 7542307
2014 CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology 44 25239835
2006 Differential engagement of modules 1 and 4 of vascular cell adhesion molecule-1 (CD106) by integrins alpha4beta1 (CD49d/29) and alphaMbeta2 (CD11b/18) of eosinophils. The Journal of biological chemistry 43 16943205
1998 Adhesion molecule mechanisms mediating monocyte migration through synovial fibroblast and endothelium barriers: role for CD11/CD18, very late antigen-4 (CD49d/CD29), very late antigen-5 (CD49e/CD29), and vascular cell adhesion molecule-1 (CD106). Journal of immunology (Baltimore, Md. : 1950) 43 9552005
2009 Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy. Investigative ophthalmology & visual science 42 19553613
1994 Regulated expression of p150,95 (CD11c/CD18; alpha X/beta 2) and VLA-4 (CD49d/CD29; alpha 4/beta 1) integrins during myeloid cell differentiation. European journal of immunology 41 8020569
2003 In vivo exit of c-kit+/CD49d(hi)/beta7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis. Blood 40 14604954
2001 Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment. American journal of physiology. Lung cellular and molecular physiology 38 11238023
1995 Domains 1 and 4 of vascular cell adhesion molecule-1 (CD106) both support very late activation antigen-4 (CD49d/CD29)-dependent monocyte transendothelial migration. Journal of immunology (Baltimore, Md. : 1950) 36 7545712
2014 Microenvironmental interactions in chronic lymphocytic leukemia: the master role of CD49d. Seminars in hematology 35 25048781
2017 CD11a and CD49d enhance the detection of antigen-specific T cells following human vaccination. Vaccine 34 28662951
2017 NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways. Leukemia 34 28935990
1997 Clustering the adhesion molecules VLA-4 (CD49d/CD29) in Jurkat T cells or VCAM-1 (CD106) in endothelial (ECV 304) cells activates the phosphoinositide pathway and triggers Ca2+ mobilization. European journal of immunology 34 9209507
1996 Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages. Leukemia 34 8709639
2023 Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis. Gastroenterology 33 38154529
2011 CD49d expression as a promising biomarker to monitor natalizumab efficacy. Journal of the neurological sciences 31 22050952
2003 C5 is required for CD49d expression on neutrophils and VCAM expression on vascular endothelial cells following mesenteric ischemia/reperfusion. Clinical immunology (Orlando, Fla.) 30 12584052
2001 Post-mortem markers of sepsis: an immunohistochemical study using VLA-4 (CD49d/CD29) and ICAM-1 (CD54) for the detection of sepsis-induced lung injury. International journal of legal medicine 30 11355415
2002 Rolling adhesion of human NK cells to porcine endothelial cells mainly relies on CD49d-CD106 interactions. Transplantation 28 11907429
2000 Glucocorticoid receptor activation reduces CD11b and CD49d levels on murine eosinophils: characterization and functional relevance. American journal of respiratory cell and molecular biology 28 10837366
1999 The role of alpha4 (CD49d) and beta2 (CD18) integrins in eosinophil and neutrophil migration to allergic lung inflammation in the Brown Norway rat. American journal of respiratory cell and molecular biology 27 10030843
1991 ICAM-2 peptides mediate lymphocyte adhesion by binding to CD11a/CD18 and CD49d/CD29 integrins. FEBS letters 27 1709118
2019 Integrative transcriptomic and proteomic analysis reveals CD9/ITGA4/PI3K-Akt axis mediates trabecular meshwork cell apoptosis in human glaucoma. Journal of cellular and molecular medicine 24 31680442
2013 Cooperativity of CD44 and CD49d in leukemia cell homing, migration, and survival offers a means for therapeutic attack. Journal of immunology (Baltimore, Md. : 1950) 24 24127558
2006 In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance. European journal of immunology 24 17039568
2010 ADAM2 interactions with mouse eggs and cell lines expressing α4/α9 (ITGA4/ITGA9) integrins: implications for integrin-based adhesion and fertilization. PloS one 23 21060781
2002 Adhesion to fibronectin via alpha4 integrin (CD49d) protects B cells from apoptosis induced by serum deprivation but not via IgM or Fas/Apo-1 receptors. Clinical and experimental immunology 23 11966761
2017 CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia. British journal of haematology 22 28386906
2008 Plasma from patients with sepsis up-regulates the expression of CD49d and CD64 on blood neutrophils. American journal of respiratory cell and molecular biology 22 19011162
2015 CD49d (ITGA4) expression is a predictor of time to first treatment in patients with chronic lymphocytic leukaemia and mutated IGHV status. British journal of haematology 21 26559905
1992 Regulation of T cell proliferation by anti-CD49d and anti-CD29 monoclonal antibodies. Journal of leukocyte biology 21 1383369
2011 LPAR1 and ITGA4 regulate peripheral blood monocyte counts. Human mutation 20 21598361
1998 Importance of CD49d-VCAM interactions in human monocyte adhesion to porcine endothelium. Xenotransplantation 20 9507736
2005 RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters. Immunobiology 19 16164020
1998 CD49d expression and function on allergen-stimulated T cells from blood and airway. American journal of respiratory cell and molecular biology 19 9476917
2017 Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients. Cytometry. Part B, Clinical cytometry 18 28378895
2017 Expansion of CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 18 28455608
2015 CD49d is a disease progression biomarker and a potential target for immunotherapy in Duchenne muscular dystrophy. Skeletal muscle 18 26664665
2014 CD49d Treg cells with high suppressive capacity are remarkably less efficient on activated CD45RA- than on naive CD45RA+ Teff cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 25060807
2021 CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection. International immunology 17 33914894
2012 Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1α and MCP-1 in GM-CSF-treated human primary eosinophils. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 17 22731992
2003 Differential roles of VLA-4(CD49d/CD29) and LFA-1(CD11a/CD18) integrins and E- and P-selectin during developing and established active or adoptively transferred adjuvant arthritis in the rat. Immunology and cell biology 17 12969328
2011 The CD49d+/high subpopulation from isolated human breast sarcoma spheres possesses tumor-initiating ability. International journal of oncology 16 22159714
2007 ITGA4 polymorphisms and susceptibility to multiple sclerosis. Journal of neuroimmunology 16 17689671
2001 Intrinsic AHR in IL-5 transgenic mice is dependent on CD4(+) cells and CD49d-mediated signaling. American journal of physiology. Lung cellular and molecular physiology 16 11504693
2000 CD4(+)CD45RO(+)CD49d(high) cells are involved in the pathogenesis of relapsing-remitting multiple sclerosis. Journal of neuroimmunology 15 11063841
2010 The role of 9-O-acetylated ganglioside D3 (CD60) and {alpha}4{beta}1 (CD49d) expression in predicting the survival of patients with Sezary syndrome. Haematologica 14 20663947
2020 ITGA4 gene methylation status in chronic lymphocytic leukemia. Future science OA 13 32802392
2016 MiR-30s Family Inhibit the Proliferation and Apoptosis in Human Coronary Artery Endothelial Cells Through Targeting the 3'UTR Region of ITGA4 and PLCG1. Journal of cardiovascular pharmacology 13 27464494
2009 Association of the alpha4 integrin subunit gene (ITGA4) with autism. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 13 19259978
2005 Hyaluronate receptor (CD44) and integrin alpha4 (CD49d) are up-regulated on T cells during MS relapses. Journal of neuroimmunology 13 15990174
2025 Triple knockdown of CD11a, CD49d, and PSGL1 in T cells reduces CAR-T cell toxicity but preserves activity against solid tumors in mice. Science translational medicine 12 39841806
2023 Detection of DNA Methylation in Gene Loci ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671 for Diagnosis of Cervical Cancer. Cancer management and research 12 37457377
2022 Candesartan Reduces Neuronal Apoptosis Caused by Ischemic Stroke via Regulating the FFAR1/ITGA4 Pathway. Mediators of inflammation 12 36117589
2022 Lymph Node Metastasis-Related Gene ITGA4 Promotes the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Regulating Tumor Immune Microenvironment. Journal of oncology 12 36254221
2018 A Novel Association of Polymorphism in the ITGA4 Gene Encoding the VLA-4 α4 Subunit with Increased Risk of Alzheimer's Disease. Mediators of inflammation 12 29769839
2022 The early predictive effect of low expression of the ITGA4 in colorectal cancer. Journal of gastrointestinal oncology 11 35284127
2003 CD49d overexpression and T cell autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 11 12847241
2019 CD49d/CD29-integrin controls the accumulation of plasmacytoid dendritic cells into the CNS during neuroinflammation. European journal of immunology 10 31318439
2019 Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination. Cells 10 31861635
2008 Identification of ITGA4/ITGB7 and ITGAE/ITGB7 expressing subsets of decidual dendritic-like cells within distinct microdomains of the pregnant mouse uterus. Biology of reproduction 10 18562709
2001 Low oxygen tension and autologous plasma enhance T-cell proliferation and CD49d expression density in serum-free media. Cytotherapy 10 11953028
2018 In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment. Annals of hematology 9 29955944
2016 Functional and Clinical Significance of the Integrin Alpha Chain CD49d Expression in Chronic Lymphocytic Leukemia. Current cancer drug targets 9 27514846
2022 FEV Maintains Homing and Expansion by Activating ITGA4 Transcription in Primary and Relapsed AML. Frontiers in oncology 8 35875066
2021 Reduced frequency and functional potency of CD49d- T regulatory cells in patients with newly diagnosed type 2 diabetes mellitus. Immunobiology 8 34247018
2018 Identification of Human B-1 Helper T Cells With a Th1-Like Memory Phenotype and High Integrin CD49d Expression. Frontiers in immunology 8 30061889
2013 Increasing the ex vivo antigen-specific IFN-γ production in subpopulations of T cells and NKp46+ cells by anti-CD28, anti-CD49d and recombinant IL-12 costimulation in cattle vaccinated with recombinant proteins from Mycobacterium avium subspecies paratuberculosis. Veterinary immunology and immunopathology 8 24034934
2003 Alpha4-integrin (CD49d) expression on bovine peripheral blood neutrophils is related to inflammation of the respiratory system. Veterinary immunology and immunopathology 8 12753772
1999 Expression of the adhesion molecules CD49d and CD49e on G-CSF-mobilized CD34+ cells of patients with solid tumors or non-Hodgkin's and Hodgkin's lymphoma and of healthy donors is inversely correlated with the amount of mobilized CD34+ cells. Journal of hematotherapy & stem cell research 8 10791904
2019 MS CD49d+CD154+ Lymphocytes Reprogram Oligodendrocytes into Immune Reactive Cells Affecting CNS Regeneration. Cells 7 31775315
2017 Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies. PloS one 7 29117236

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