Affinage

ITGA4

Integrin alpha-4 · UniProt P13612

Length
1032 aa
Mass
114.9 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITGA4 (CD49d) encodes the α4 integrin subunit that pairs with β1 (forming VLA-4/α4β1) or β7 to mediate leukocyte adhesion, rolling, firm attachment, and transendothelial migration through binding to VCAM-1 and fibronectin CS-1, with the ligand-binding site mapped to α4 residues 108–268 and a critical contribution from β1-Asp130 (PMID:7531439). VLA-4 ligation activates the phosphoinositide/Ca²⁺ signaling cascade (PMID:9209507), costimulates TCR-dependent activation of NF-AT, AP-1, and NF-κB transcription factors with cytokine secretion (PMID:8757316), and delivers anti-apoptotic survival signals in germinal center B cells and leukemia cells through cooperation with CD44, CD38, and tetraspanins (CD81/CD82/CD63/CD53) that connect to FAK, Src, lck, and paxillin signaling networks (PMID:7511659, PMID:24127558, PMID:22289918, PMID:8757325). ITGA4 expression is transcriptionally regulated by RUNX3, the NOTCH1–NF-κB axis, and FEV, epigenetically controlled by promoter CpG methylation, and post-transcriptionally stabilized by METTL3-mediated m6A modification, with its functional output governing diverse processes including inflammatory cell recruitment to lung, CNS, and bone marrow, hematopoietic stem/progenitor cell mobilization, AML homing and engraftment, and CAF-driven acinar-to-ductal metaplasia via a LAMA5/ITGA4/STAT3 axis (PMID:28935990, PMID:24068493, PMID:36266324, PMID:31318439, PMID:38154529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Establishing that VLA-4–VCAM-1 engagement delivers a direct anti-apoptotic signal showed the integrin has a signaling function beyond simple adhesion, as disruption of follicular dendritic cell–B cell contacts with anti-CD49d or anti-VCAM-1 induced germinal center B cell apoptosis while purified VCAM-1 rescued survival.

    Evidence mAb-mediated disruption of FDC–B cell clusters and adhesion to immobilized VCAM-1, apoptosis assays in primary human tonsil GC B cells

    PMID:7511659

    Open questions at the time
    • Downstream survival signaling molecules not identified
    • Whether β7 pairing can substitute for β1 in this context unknown
  2. 1995 High

    Mapping the ligand-binding determinants to α4 residues 108–268 and β1-Asp130 resolved which structural regions are responsible for dual recognition of VCAM-1 and fibronectin CS-1, establishing that the two ligands share overlapping binding mechanisms.

    Evidence Interspecies α4 chimeras, function-blocking mAb epitope mapping, D130A β1 mutagenesis with adhesion assays

    PMID:7531439

    Open questions at the time
    • Atomic-resolution structure of the α4β1–ligand interface not determined
    • Relative contribution of each epitope to affinity not quantified
  3. 1995 High

    Demonstrating that monocyte transendothelial migration across activated endothelium can proceed via VLA-4/VCAM-1 independently of CD18 integrins established an alternative adhesion cascade for leukocyte extravasation, with VCAM-1 domains 1 and 4 acting as independent docking sites.

    Evidence Domain-specific VCAM-1 blocking mAbs, CD18 and α4 blocking in transendothelial migration assays across CHO-VCAM transfectants and IL-1-activated HUVEC

    PMID:7542307 PMID:7545712

    Open questions at the time
    • Whether domain-1 and domain-4 engage the same α4 epitope or distinct sites not resolved
    • Relative contribution of α4β7 vs. α4β1 in this transmigration not tested
  4. 1996 High

    Showing that VLA-4 ligation activates the phosphoinositide pathway and triggers bidirectional Ca²⁺ signaling between T cells and endothelial cells revealed that VLA-4 engagement initiates classical second-messenger cascades, while the finding that VLA-4 costimulates NF-AT, AP-1, and NF-κB downstream of TCR established its role as a bona fide T cell costimulatory molecule.

    Evidence Spectrofluorimetry/confocal Ca²⁺ imaging with Fura-2, IP3 assays in Jurkat cells; EMSA for transcription factors and cytokine ELISA with co-immobilized VCAM-1/CS-1 in primary T cells

    PMID:8757316 PMID:9209507

    Open questions at the time
    • Proximal kinase linking VLA-4 to PLC/IP3 not identified
    • Whether costimulation requires sustained adhesion or transient ligation not tested
  5. 1996 High

    Discovery that tetraspanins CD81, CD82, CD63, and CD53 specifically associate with α4β1 through the ligand-competent extracellular domain of α4—independently of the cytoplasmic tail—revealed a supramolecular organization principle in which tetraspanin-enriched microdomains scaffold integrin signaling platforms.

    Evidence Reciprocal co-immunoprecipitation, confocal co-localization, adhesion-deficient α4 mutants (D346E, D408E) and cytoplasmic-tail deletion constructs

    PMID:8757325

    Open questions at the time
    • Functional consequence of tetraspanin association for downstream signaling not directly tested
    • Stoichiometry and direct vs. bridged interaction not resolved
  6. 1997 High

    Intrapulmonary anti-CD49d blockade inhibited airway eosinophilia, cytokine release, mucus production, and hyperresponsiveness in allergic mice—while systemic blockade only affected eosinophilia—identifying a CD49d-positive intrapulmonary effector cell as the critical mediator of allergen-induced airway inflammation.

    Evidence Intranasal vs. intraperitoneal anti-CD49d mAb in ovalbumin-sensitized mouse model; BAL counts, cytokines, methacholine challenge

    PMID:9399955

    Open questions at the time
    • Identity of the intrapulmonary CD49d+ effector cell not definitively established
    • Whether α4β7 contributes in addition to α4β1 not distinguished
  7. 2001 High

    Showing that α4β1 and α5β1 mediate β2-integrin-independent neutrophil recruitment to inflamed lung parenchyma via combinatorial mAb blocking expanded the paradigm that β1 integrins serve as an alternative neutrophil emigration pathway in tissue-specific inflammation.

    Evidence Intratracheal LPS in rats, myeloperoxidase assay, BAL counts, combined anti-α4/anti-α5/anti-β2 mAb blocking

    PMID:11254723

    Open questions at the time
    • Specific ligand(s) engaged by α4β1 on pulmonary endothelium/matrix not identified
    • Kinetics of α4 vs. β2 utilization during disease progression not studied
  8. 2004 High

    Demonstrating that CD49d is required for chemokine-induced neutrophil mobilization from bone marrow—with >75% dependence—while CD18 promotes retention established opposing roles for these integrins in controlling the bone marrow neutrophil reserve.

    Evidence In situ perfusion of rat femoral bone marrow with MIP-2, blocking mAbs and CD49d antagonist

    PMID:15542579

    Open questions at the time
    • Specific VCAM-1 or other stromal ligand mediating retention not identified
    • Whether this mechanism applies to other hematopoietic lineages not tested
  9. 2005 Medium

    Identification of RUNX3 as a transcriptional activator of the ITGA4 promoter provided the first transcription-factor-level explanation for CD49d upregulation during dendritic cell maturation.

    Evidence CD49d promoter transactivation assay, RUNX3 overexpression, Northern/RT-PCR in maturing monocyte-derived DCs

    PMID:16164020

    Open questions at the time
    • RUNX3 binding site in the ITGA4 promoter not mapped by ChIP
    • Whether RUNX3 is necessary (loss-of-function) not tested
  10. 2006 High

    Resolving that VCAM-1 module 1 is engaged exclusively by α4β1 while module 4 is engaged by both α4β1 and αMβ2 clarified the molecular basis of module-specific adhesion and revealed PI3K-dependent regulation of the module-4 pathway, with IL-5 shifting integrin usage toward αMβ2.

    Evidence Defined VCAM-1 module constructs, mAb blocking, PI3K inhibitors, eosinophilic cell lines lacking αMβ2, primary eosinophils

    PMID:16943205

    Open questions at the time
    • Structural basis for module specificity not determined
    • Whether PI3K acts on integrin activation state or surface expression not resolved
  11. 2009 High

    Discovering that CD38 constitutively associates with CD49d in CLL and enhances VCAM-1 adhesion, Vav-1 phosphorylation, and survival signaling explained the synergistic prognostic impact of CD38+CD49d+ co-expression in CLL.

    Evidence Cocapping, co-immunoprecipitation, CD38 transfection into Mec-1 cells, adhesion/apoptosis assays, pVav-1 immunoblot in primary CLL

    PMID:22289918

    Open questions at the time
    • Whether CD38 enzymatic activity is required or just its physical presence not resolved
    • Structural interface between CD38 and α4β1 unknown
  12. 2013 High

    Elucidating that CD44 and CD49d cooperate through ligand-induced proximity to share downstream kinases (FAK, Src, paxillin, lck→MAPK)—requiring intact cytoplasmic tails of both—and that combined blockade dislodges leukemia cells in vivo, provided a mechanistic framework for adhesion-based therapeutic targeting.

    Evidence Mutagenesis of CD49d (FAK-binding/phosphorylation sites) and CD44 (ezrin-binding/tail-truncated) in lymphoma/Jurkat cells, Co-IP, in vivo adhesion/migration assays

    PMID:24127558

    Open questions at the time
    • Direct structural contact between CD44 and CD49d not demonstrated
    • Relative contribution of each kinase to survival vs. migration not dissected
  13. 2013 High

    Demonstrating that ITGA4 promoter CpG methylation inversely controls CD49d expression—with demethylation rescuing expression—established an epigenetic layer of ITGA4 regulation and linked trisomy 12 CLL to constitutive CD49d overexpression via hypomethylation.

    Evidence Bisulfite genomic sequencing, 5-aza-2′-deoxycytidine demethylation rescue, flow cytometry across ~1200 CLL cases

    PMID:24068493

    Open questions at the time
    • Which specific CpG sites are functionally decisive not narrowed down
    • Methyltransferase(s) responsible not identified
  14. 2017 High

    Identifying a NOTCH1→NF-κB→CD49d transcriptional axis in CLL explained how gain-of-function NOTCH1 mutations drive CD49d overexpression and the associated aggressive clinical phenotype.

    Evidence NOTCH1 intracellular domain stable transfection in MEC-1, NOTCH1/NF-κB pharmacological inhibitors, NF-κB nuclear translocation assay, primary CLL with mutated NOTCH1

    PMID:28935990

    Open questions at the time
    • Whether NF-κB binds the ITGA4 promoter directly or through intermediary factors not shown
    • Contribution of non-canonical NF-κB not assessed
  15. 2018 High

    Showing that BCR signaling triggers VLA-4 inside-out activation through a PI3K-dependent, BTK-independent mechanism—and that ibrutinib reduces but cannot fully suppress this—revealed why CD49d+ CLL may resist BTK-inhibitor therapy through sustained adhesion.

    Evidence Inside-out VLA-4 activation assays, ibrutinib treatment, PI3K/BTK inhibitors, in vivo models, three independent clinical CLL cohorts

    PMID:29301866

    Open questions at the time
    • Identity of the PI3K isoform responsible not determined
    • Whether this mechanism operates in other B cell malignancies not tested
  16. 2022 High

    Discovery that METTL3-mediated m6A methylation stabilizes ITGA4 mRNA, increasing protein expression and AML homing/engraftment, introduced a post-transcriptional regulatory layer and identified METTL3 inhibition as a strategy to target ITGA4-dependent leukemia–niche interactions.

    Evidence METTL3 knockdown/overexpression, mRNA stability assays, m6A profiling, in vivo xenograft homing models, METTL3 inhibitor treatment

    PMID:36266324

    Open questions at the time
    • Specific m6A site(s) on ITGA4 mRNA not mapped
    • m6A reader protein mediating stabilization not identified
  17. 2023 High

    Identification of a CAF-secreted LAMA5/ITGA4/STAT3 axis driving acinar-to-ductal metaplasia expanded ITGA4 function beyond immune cell biology into stromal-epithelial crosstalk in early pancreatic carcinogenesis.

    Evidence LC-MS/MS proteomics, RNA-seq, ITGA4 knockdown, acinar organoid/explant co-culture, KC and KPC mouse models

    PMID:38154529

    Open questions at the time
    • Whether ITGA4 pairs with β1 or β7 in acinar cells not specified
    • Downstream STAT3 targets mediating ADM not identified
    • Whether ITGA4 blockade prevents tumor progression beyond ADM not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of the full α4β1 ectodomain in complex with VCAM-1 or fibronectin CS-1 remains unresolved, and the precise mechanisms by which tetraspanin and CD38/CD44 supramolecular assemblies organize α4β1 signaling at the nanoscale are still unknown.
  • No atomic-resolution α4β1–ligand co-structure
  • Nanoscale organization of the α4β1–tetraspanin–CD38–CD44 signaling platform unresolved
  • Relative in vivo contributions of α4β1 vs. α4β7 in most tissue contexts not systematically addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 5 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 5 R-HSA-1500931 Cell-Cell communication 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CD38CD44CD81CD82ITGB1ITGB7PTK2VCAM1
Complex memberships
Tetraspanin-enriched microdomain (CD81/CD82/CD63/CD53–α4β1)VLA-4 (α4β1 integrin)α4β7 integrin

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The ligand-binding sites of integrin α4β1 (CD49d/CD29) for VCAM-1 and fibronectin CS-1 were mapped to residues 108–268 of the α4 subunit using interspecies chimeras; epitopes B1 (residues 195–268) and B2 (residues 108–182) were associated with ligand binding, while Asp-130 of β1 was shown to be critical for binding to both VCAM-1 and CS-1, indicating shared binding mechanisms for the two ligands. Interspecies α4 chimeras expressed in mammalian cells, anti-α4 function-blocking mAb epitope mapping, D130A β1 mutagenesis with adhesion assays The Biochemical journal High 7531439
1996 Transmembrane-4 superfamily proteins CD81, CD82, CD63, and CD53 specifically associate with integrin α4β1 (CD49d/CD29) as demonstrated by reciprocal co-immunoprecipitation and confocal co-localization; the association requires a ligand-competent α4 extracellular domain (abolished by adhesion-deficient D346E and D408E mutants) but is independent of the α4 cytoplasmic domain or divalent cations. Reciprocal co-immunoprecipitation, confocal microscopy, α4 adhesion-deficient point mutants (D346E, D408E) and cytoplasmic-domain deletion constructs Journal of immunology High 8757325
1994 VLA-4 (CD49d/CD29)-VCAM-1 adhesion prevents apoptosis of germinal center B cells; disruption of FDC–B cell clusters with anti-CD49d or anti-VCAM-1 mAb induces apoptosis, and adhesion to plastic-coated VCAM-1 diminishes apoptosis and synergizes with anti-IgM. mAb-mediated disruption of FDC–B cell clusters, adhesion to purified immobilized VCAM-1, apoptosis assays on human tonsil-derived GC B cells Journal of immunology High 7511659
1996 VLA-4 (CD49d/CD29) ligation on Jurkat T cells activates the phosphoinositide pathway and triggers a biphasic intracellular Ca2+ response; cross-linking of its counter-receptor VCAM-1 on endothelial cells produces the same Ca2+ mobilization, and cell–cell contact via VLA-4/VCAM-1 elicits mutual Ca2+ signaling in both cell types. Cross-linked anti-α4 mAb treatment of Jurkat cells and ECV 304 endothelial cells, spectrofluorimetry/confocal Ca2+ imaging with Fura-2, inositol 1,4,5-trisphosphate production assay European journal of immunology High 9209507
1996 α4β1 (CD49d/CD29) co-immobilized with anti-CD3 mAb costimulates freshly isolated human T cells to induce NF-AT, AP-1, and NF-κB transcription factor binding and secretion of IL-2, TNF-α, IFN-γ, and GM-CSF; α4β1 ligation alone is insufficient and does not alter the TCR activation threshold, indicating a distinct synergistic signaling pathway. Electromobility shift assays for transcription factors, cytokine ELISA, dose–response anti-CD3 titration with co-immobilized VCAM-1 or fibronectin CS-1, primary human peripheral blood T cells Journal of immunology High 8757316
1994 VLA-4 (CD49d/CD29)-mediated adhesion to fibronectin augments stimulated eosinophil degranulation (eosinophil peroxidase release); blocking CD49d with anti-VLA-4 mAb HP2/1 attenuates both fibronectin adhesion and EPO secretion induced by fMLF + cytochalasin B. Anti-VLA-4 mAb (HP2/1) blocking, eosinophil adhesion assay on FN-coated plates, eosinophil peroxidase release assay, primary human eosinophils American journal of respiratory cell and molecular biology Medium 8049081
1995 VLA-4 (CD49d/CD29) on monocytes mediates transendothelial migration across IL-1-activated endothelium via VCAM-1 domains 1 and 4 independently of CD18; domain-1 mAb alone nearly completely blocks this CD18-independent migration, and combined domain-1 plus domain-4 blockade achieves complete inhibition. Monocyte transendothelial migration assay across CHO-VCAM transfectants and IL-1-activated HUVEC, domain-specific VCAM-1 blocking mAbs, CD18 and α4 blocking mAbs Journal of immunology High 7545712
1995 Upon IL-1 activation of endothelium, monocyte transendothelial migration in response to C5a, MIP-1α, RANTES, and PAF becomes CD18-independent and instead requires CD49d (VLA-4); combined anti-CD49d plus anti-CD18 fully blocks migration, whereas migration to MCP-1 is inhibited by endothelium-derived MCP-1 acting as an autocrine brake. mAb blocking of CD18 and α4 (CD49d) in chemokine-driven monocyte transendothelial migration assay, neutralization of HUVE-conditioned MCP-1 Journal of leukocyte biology High 7542307
1997 Local intrapulmonary blockade of CD49d (α4 integrin) by intranasal mAb inhibits airway eosinophilia, IL-4/IL-5 release, mucus production, and hyperresponsiveness in allergic mice, whereas systemic (intraperitoneal) CD49d blockade only prevents eosinophilia; this identifies a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil as the key effector cell of allergen-induced pulmonary inflammation. Intranasal vs. intraperitoneal anti-CD49d mAb administration in ovalbumin-sensitized mouse asthma model; BAL cell counts, cytokine measurement, methacholine challenge The Journal of clinical investigation High 9399955
2000 CD49d integrin expression is induced/upregulated during TNF-α– or LPS-induced maturation of monocyte-derived dendritic cells in an NF-κB– and p38 MAPK–dependent manner; upregulated CD49d confers mature MDDC with enhanced adhesion to fibronectin CS-1 and mediates their transendothelial migration. Northern blot and flow cytometry for CD49d during MDDC maturation, NF-κB inhibitor (N-acetylcysteine), p38 inhibitor (SB203580), MEK1/2 inhibitor (PD98059), adhesion assay to CS-1, transendothelial migration assay Journal of immunology High 11035069
2002 α4 integrin (CD49d)-mediated adhesion of B cells to fibronectin fragment H89 (α4β1 ligand) or FN-III4-5 protects against serum deprivation-induced apoptosis but not against IgM-triggered or Fas-mediated apoptosis; protection is reversed by anti-α4 mAb, indicating pathway-specific anti-apoptotic signaling. Adhesion of B cell lines (Ramos, Nalm-6, EHEB, IM-9) to recombinant fibronectin fragments H89 and FN-III4-5, viability assay, anti-α4 mAb blocking, comparison across three apoptosis induction pathways Clinical and experimental immunology Medium 11966761
2002 Human NK cell rolling adhesion to porcine endothelial cells is mediated predominantly (>75% inhibition) by CD49d–CD106 (VLA-4/VCAM-1) interactions; static firm adhesion and transendothelial migration are also substantially dependent on CD49d–CD106 in addition to CD11a. Shear-stress flow adhesion assay and static adhesion assay with blocking mAbs to CD49d, CD106, CD62L, CD11a/CD18 on human NK cells and porcine EC; NK92 (FcγRIII–) cell line used to exclude Fc-dependent binding Transplantation Medium 11907429
2004 MIP-2-stimulated neutrophil mobilization from rat bone marrow is >75% dependent on CD49d; blockade of CD49d with neutralizing mAb or a specific antagonist dramatically inhibits chemokine-induced neutrophil release, while CD18 blockade paradoxically increases release, revealing contrasting roles for CD49d (in release) and CD18 (in retention). In situ perfusion of rat femoral bone marrow, blocking mAbs against CD49d and CD18, CD49d antagonist, neutrophil enumeration Blood High 15542579
2006 Eosinophil adhesion to VCAM-1 module 1 (in 6d-VCAM-1 and 1-3VCAM-1 constructs) is mediated exclusively by α4β1 (CD49d/CD29), whereas adhesion to module 4 (4-7VCAM-1) is mediated by both α4β1 and αMβ2 (CD11b/CD18); PI3K inhibitors selectively block module-4-mediated adhesion, and IL-5 activation shifts dominance to αMβ2. Anti-α4, anti-αM, anti-β1, anti-CD18 mAb blocking; PI3K inhibitors; eosinophilic cell lines lacking αMβ2; static and flow adhesion assays with defined VCAM-1 module constructs; primary blood eosinophils The Journal of biological chemistry High 16943205
2005 RUNX3 transcriptionally activates the CD49d (α4 integrin) gene promoter; RUNX3 overexpression correlates with increased CD49d mRNA and protein during monocyte-derived dendritic cell maturation, establishing RUNX3 as a transcriptional regulator of ITGA4 expression. CD49d promoter transactivation assay, RUNX3 overexpression, Northern/RT-PCR correlation in maturing MDDC Immunobiology Medium 16164020
2006 CD44 and CD49d physically associate in activated lymphocytes in vivo; this association allows CD44 to access FAK and allows CD49d to access lck and ezrin, so that ligand engagement of either molecule activates downstream kinases of both, synergistically enhancing lymphocyte motility, proliferation, and apoptosis resistance in autoimmune disease. Co-immunoprecipitation, anti-CD44 and anti-CD49d mAb blocking, co-culture/motility assays, draining LNC from murine alopecia areata model European journal of immunology Medium 17039568
2009 The CD49d/CD29 integrin complex and CD38 are constitutively physically associated in primary CLL cells; CD38 enhances CD49d-mediated cell adhesion to VCAM-1 and fibronectin fragments, promotes Vav-1 phosphorylation and F-actin redistribution at adhesion sites, and increases apoptosis resistance in adherent CD49d+CD38+ vs. CD49d+CD38− cells. Cocapping, co-immunoprecipitation, CD38 transfection into CD49d+CD38− Mec-1 cells, adhesion assays on VCAM-1/fibronectin substrates, pVav-1 immunoblot, F-actin staining, apoptosis assays Leukemia High 22289918
2013 CD44 and CD49d cooperate in leukemia cell adhesion, migration, and apoptosis resistance by ligand-induced proximity that grants both molecules shared access to Src, FAK, paxillin, and via lck to the MAPK pathway; antiapoptotic molecule liberation requires wild-type cytoplasmic tails of both proteins; combined anti-CD44 plus anti-CD49d efficiently dislodges leukemia cells from bone marrow and spleen and enhances chemotherapy. CD49d transfection with point-mutated (FAK-binding and phosphorylation site ablated) variants into CD49d− EL4 lymphoma, CD44 transfection with ezrin-binding and tail-truncated mutants into CD44− Jurkat; ligand-blocking assays, FAK/Src/paxillin co-IP, in vitro/in vivo adhesion/migration/apoptosis assays Journal of immunology High 24127558
2017 NOTCH1 pathway activation drives CD49d expression in CLL via NF-κB; stable transfection of the NOTCH1 intracellular domain into MEC-1 cells increases CD49d expression, pharmacological inhibition of NOTCH1 and/or NF-κB reduces NF-κB nuclear translocation and downmodulates CD49d, establishing a NOTCH1→NF-κB→CD49d regulatory axis. NOTCH1 intracellular domain stable transfection in MEC-1 cells, NOTCH1 and NF-κB pharmacological inhibitors, NF-κB nuclear translocation assay, CD49d flow cytometry and mRNA in primary CLL with mutated/wild-type NOTCH1 Leukemia High 28935990
2018 VLA-4 (CD49d/CD29) undergoes inside-out activation upon BCR triggering in CD49d-positive CLL, reinforcing adhesion; ibrutinib reduces constitutive VLA-4 activation and adhesion but this can be overcome by exogenous BCR stimulation through a BTK-independent, PI3K-dependent mechanism. Inside-out VLA-4 activation assay, adhesion assays in vitro and in vivo with ibrutinib treatment, BCR crosslinking, BTK inhibition, PI3K inhibition, clinical CD49d expression monitoring in three ibrutinib-treated CLL cohorts The Journal of experimental medicine High 29301866
2022 METTL3-mediated m6A methylation extends ITGA4 mRNA half-life, increasing ITGA4 protein expression and thereby enhancing AML cell homing and engraftment in bone marrow; a METTL3 inhibitor reverses this phenotype in vitro and in vivo. RNA sequencing, reverse-phase protein arrays, METTL3 knockdown/overexpression, mRNA stability assays, m6A methylation profiling, in vivo xenograft homing/engraftment models, METTL3 inhibitor treatment Leukemia High 36266324
2022 The transcription factor FEV directly activates ITGA4 transcription in a dose-dependent manner in AML cells; FEV knockdown suppresses homing and proliferation, and natalizumab (anti-integrin α4) reduces migration and colony-forming ability of blasts and leukemic-initiating cells. FEV knockdown (AML cell lines), FEV dose-dependent ITGA4 promoter activation assay, natalizumab functional blockade of migration and colony-forming assays in primary and relapsed AML samples Frontiers in oncology Medium 35875066
2023 CAF-secreted laminin α5 engages ITGA4 on acinar cells to activate STAT3 signaling, driving acinar-to-ductal metaplasia (ADM) and pancreatic cancer initiation; the LAMA5/ITGA4/STAT3 axis was identified by integration of proteomics (CAF conditioned medium) and transcriptomics (acinar cell response), and validated by ITGA4 depletion in co-culture and mouse models. LC-MS/MS proteomics of CAF conditioned medium, RNA-seq of acinar cells, ITGA4 knockdown, confocal microscopy, immunoblotting, acinar organoid and explant co-culture with mCAFs in WT, KC, and KPC mice Gastroenterology High 38154529
2019 CD9 overexpression in trabecular meshwork cells activates ITGA4 (integrin α4), leading to PI3K and Akt activation, decreased apoptosis, and attenuation of glaucoma-related cell death; ITGA4 acts downstream of CD9 in this anti-apoptotic signaling axis. Transcriptome and proteome profiling of iHTM vs. GTM3 cells, CD9 overexpression constructs, co-IP/signaling assays for ITGA4/PI3K/Akt, apoptosis assays Journal of cellular and molecular medicine Medium 31680442
2015 CD49d-positive neutrophils expressing VEGFR1 and CXCR4 require VLA-4 (CD49d/CD29) for crawling and emigration in response to VEGF-A but not to MIP-2 (CXCL2); intravital microscopy and transplantation-based angiogenesis models show that targeting CD49d impairs proangiogenic neutrophil recruitment and vessel neoformation. Intravital microscopy of mouse microcirculation, chimeric mice with impaired VEGFR1/VEGFR2 signaling, anti-CD49d blockade in avascular pancreatic islet transplantation model, FACS-sorted CD49d+ vs. CD49d− neutrophils in adhesion and chemotaxis assays Blood High 26286848
2019 CD49d/CD29 (α4β1) integrin controls accumulation of plasmacytoid dendritic cells (pDCs) into the CNS during EAE; adoptive transfer experiments show pDCs are blood-recruited, and blocking CD49d drastically reduces CNS pDC numbers, while CD18 blockade has no effect, establishing a specific requirement for α4β1 but not β2 integrins. Adoptive transfer experiments, blocking anti-CD49d and anti-CD29 in vivo during acute EAE, flow cytometric quantification of CNS pDCs, ex vivo TLR-9 stimulation functional assay European journal of immunology High 31318439
2004 NOD mouse macrophages show defective LPS-induced upregulation of CD49d, reduced CD49d-mediated adhesion to fibronectin, and impaired migration; ERK1/2 negatively regulates macrophage CD49d expression and is hyperactive in NOD macrophages, contributing to their adhesion defect. Flow cytometry for CD49d on NOD vs. control macrophages, LPS stimulation, ERK1/2 pharmacological inhibition, fibronectin adhesion assay, peritoneal inflammation clearance assay European journal of immunology Medium 15517611
2013 CD49d promoter methylation inversely regulates CD49d expression in CLL; trisomy 12 CLL cells show near-complete absence of ITGA4 gene methylation and highest CD49d expression, while CD49d− cases are hypermethylated; treatment with the hypomethylating agent 5-aza-2′-deoxycytidine rescues CD49d expression in hypermethylated CLL cells. Bisulfite genomic sequencing of ITGA4 CpG sites, 5-aza-2′-deoxycytidine demethylation assay, flow cytometry across cytogenetic CLL groups (n=1200) Blood High 24068493
2001 α4β1 (CD49d/CD29) and α5β1 integrins mediate β2-integrin-independent neutrophil recruitment to the lung in endotoxin-induced inflammation; combined anti-α4 + anti-β2 blockade inhibits parenchymal PMNL accumulation by 56% and BALF accumulation by 58%, and adding anti-α5 further reduces parenchymal accumulation to 79% inhibition. Intratracheal LPS model in Lewis rats, myeloperoxidase assay for parenchymal PMNL, BAL cell counts, combined and single mAb blocking with anti-α4, anti-α5, anti-β2 Journal of immunology High 11254723

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 197 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
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
2018 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. The Journal of experimental medicine 82 29301866
2022 METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4. Leukemia 79 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 57 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
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
2020 CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood 48 32006000
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
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 46 25902909
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
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
2014 Microenvironmental interactions in chronic lymphocytic leukemia: the master role of CD49d. Seminars in hematology 34 25048781
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
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
2023 Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis. Gastroenterology 27 38154529
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
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
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 23 31680442
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
1998 CD49d expression and function on allergen-stimulated T cells from blood and airway. American journal of respiratory cell and molecular biology 19 9476917
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
2005 RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters. Immunobiology 18 16164020
2021 CD49d marks Th1 and Tfh-like antigen-specific CD4+ T cells during Plasmodium chabaudi infection. International immunology 17 33914894
2017 Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients. Cytometry. Part B, Clinical cytometry 17 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.] 17 28455608
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
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
2022 Candesartan Reduces Neuronal Apoptosis Caused by Ischemic Stroke via Regulating the FFAR1/ITGA4 Pathway. Mediators of inflammation 12 36117589
2020 ITGA4 gene methylation status in chronic lymphocytic leukemia. Future science OA 12 32802392
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
2023 Detection of DNA Methylation in Gene Loci ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671 for Diagnosis of Cervical Cancer. Cancer management and research 11 37457377
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 11 36254221
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
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 9 39841806
2022 The early predictive effect of low expression of the ITGA4 in colorectal cancer. Journal of gastrointestinal oncology 9 35284127
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
2021 Reduced frequency and functional potency of CD49d- T regulatory cells in patients with newly diagnosed type 2 diabetes mellitus. Immunobiology 8 34247018
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
2022 FEV Maintains Homing and Expansion by Activating ITGA4 Transcription in Primary and Relapsed AML. Frontiers in oncology 7 35875066
2018 Identification of Human B-1 Helper T Cells With a Th1-Like Memory Phenotype and High Integrin CD49d Expression. Frontiers in immunology 7 30061889
2012 Circulating CD35(-)/CD49d(+) neutrophils in influenza virus infection patients. Human immunology 7 22902398
2004 Defective up-regulation of CD49d in final maturation of NOD mouse macrophages. European journal of immunology 7 15517611