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Gene Review

ITGA4  -  integrin, alpha 4 (antigen CD49D, alpha 4...

Homo sapiens

Synonyms: CD49 antigen-like family member D, CD49D, CD49d, IA4, Integrin alpha-4, ...

Disease relevance of ITGA4

  • These changes of integrin expression during tumour progression particularly, the data showing an increase of VLA-4, and a decrease of VLA-6 expression support the concept that integrins are a new additional set of prognostic markers which indicate predisposition to the development of metastases [1].
  • LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases [2].
  • Mediastinal clear cell lymphoma of B-cell type differed from FCCL in its regular lack of VLA-3, -5, and -6 and in frequently lacking VLA-4 [3].
  • Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages [4].
  • VLA-4 affinity correlates with peripheral blood white cell count and DNA content in patients with precursor acute lymphoblastic leukemia (B-ALL). The data suggest that decreased VLA-4 activity results in increased circulating lymphoblasts [5].
  • Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression [6].

Psychiatry related information on ITGA4

  • Critical period for a teratogenic VLA-4 antagonist: Developmental effects and comparison of embryo drug concentrations of teratogenic and non-teratogenic VLA-4 antagonists [7].

High impact information on ITGA4


Chemical compound and disease context of ITGA4


Biological context of ITGA4


Anatomical context of ITGA4


Associations of ITGA4 with chemical compounds

  • Binding of small molecule ligands to VLA-4 binding pocket induces exposure of specific epitopes (Ligand Induced Binding SItes, LIBS). This conformationnal flexibility can be used for a discovery of novel integrin antagonists [25] [26].
  • Tyrosine phosphorylation of several stromal cell proteins was stimulated within 5 to 10 min of contact with either CD49d-expressing or CD49d-deficient RAMOS [27].
  • Abs to the beta(1) integrins, CD49d and CD49e, as well as to P-selectin and P-selectin glycoprotein ligand 1, inhibited basophil rolling and adhesion [28].
  • CD49d expression and function on allergen-stimulated T cells from blood and airway [13].
  • Both CD29 and CD49d clustering significantly inhibited anti-IgE-induced histamine release from the human basophil [29].
  • We observed that stimulated neutrophil CD49d expression was decreased by activation of A(2A) adenosine receptors (A(2A)AR) with the selective agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylicacid methyl ester (ATL146e; EC(50)=6.4 nM) [6].

Physical interactions of ITGA4

  • The VCAM-1 sequence G65NEH also appears to be involved in binding VLA-4 [30].
  • K562 lacked VLA-4 and a low binding affinity of the VLA-5 on these cells resulted in an absence of binding to the bone-marrow stroma [31].
  • Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4-mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes [32].
  • These results underline that the FN-binding activity of VLA-4 is dependent on processes affecting cellular activation as described for other members of the integrin family [33].
  • We postulate that the mode of action of IFN-beta therapy in MS may involve the induction of an increase in sVCAM. sVCAM could bind VLA-4 on T-cells and intercept their adhesion to the blood brain barrier (BBB) [34].

Co-localisations of ITGA4

  • However, when conjugates are formed in the presence of anti-alpha 4 antibodies, VLA-4 colocalizes with the CD3-zeta chain at the center of the synapse [35].

Regulatory relationships of ITGA4

  • VLA-4 dependent cell adhesion is regulated by G-protein coupled receptors. Activation of Gαi- coupled receptors (CXCR4 or formyl peptide receptor) results in up-regulation of VLA-4 affinity for the ligand and stimulates cell adhesion. Activation of Gαs-coupled receptors (β2-adrenergic receptor or histamine receptor H2) leads to affinity down-regulation and promote cell de-adhesion [36]
  • The CD18- and VLA-4-independent migration across HSF was completely inhibited by mAb to alpha5 of VLA-5 [37].
  • VLA-4 on Jurkat cells is of constitutively high avidity and interfered with migration across barriers expressing VCAM-1 [21].
  • The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses [38].
  • VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients [39].
  • Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site [32].

Other interactions of ITGA4

  • This binding was blocked by mAbs to the VLA alpha-subunits alpha 6 (CD49f), or alpha 5 (CD49e) and alpha 4 (CD49d), respectively [40].
  • An alternative leukocyte homotypic adhesion mechanism, LFA-1/ICAM-1-independent, triggered through the human VLA-4 integrin [20].
  • Additive inhibition of adherence to unstimulated human umbilical vein endothelium (HUVE) was observed when monocytes were pretreated with both MoAb to CD49d and MoAb to CD18, the common beta-chain of the leukocyte beta 2 integrin receptors [41].
  • These data further demonstrate that CDE maturing in the continued presence of IL-5 adhere to HUVEC predominantly through VLA-4 ligation [42].
  • Adherence of monocytes to HUVE stimulated by recombinant human tumor necrosis factor-alpha was not reduced by MoAbs to CD18, CD49d, or ELAM-1 when used singly, but combinations of these MoAbs produced significant inhibition [41].

Analytical, diagnostic and therapeutic context of ITGA4


  1. Tumour progression and metastatic behaviour in vivo correlates with integrin expression on melanocytic tumours. Schadendorf, D., Gawlik, C., Haney, U., Ostmeier, H., Suter, L., Czarnetzki, B.M. J. Pathol. (1993) [Pubmed]
  2. Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Yusuf-Makagiansar, H., Anderson, M.E., Yakovleva, T.V., Murray, J.S., Siahaan, T.J. Medicinal research reviews. (2002) [Pubmed]
  3. Adhesion molecules VLA-1 to VLA-6 define discrete stages of peripheral B lymphocyte development and characterize different types of B cell neoplasia. Möller, P., Eichelmann, A., Koretz, K., Mechtersheimer, G. Leukemia (1992) [Pubmed]
  4. Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages. Eksioğlu-Demiralp, E., Alpdoğan, O., Aktan, M., Firatli, T., Oztürk, A., Budak, T., Bayik, M., Akoğlu, T. Leukemia (1996) [Pubmed]
  5. VLA-4 affinity correlates with peripheral blood white cell count and DNA content in patients with precursor B-ALL. Blenc, A.M., Chiagev, A., Sklar, L., Larson, R.S. Leukemia. (2003) [Pubmed]
  6. Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. Sullivan, G.W., Lee, D.D., Ross, W.G., DiVietro, J.A., Lappas, C.M., Lawrence, M.B., Linden, J. J. Leukoc. Biol. (2004) [Pubmed]
  7. Critical period for a teratogenic VLA-4 antagonist: Developmental effects and comparison of embryo drug concentrations of teratogenic and non-teratogenic VLA-4 antagonists. Crofts, F., Rohatagi, S., Pino, M., DeLise, B., Zhang, J., Nguyen, M., Guittin, P., Barbellion, S., Brunel, P., Hofmann, T., Schmidt, J., Wong, M., Lockey, P., Lerman, S., Clark, R. Birth Defects Res. B Dev. Reprod. Toxicol. (2004) [Pubmed]
  8. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Elices, M.J., Osborn, L., Takada, Y., Crouse, C., Luhowskyj, S., Hemler, M.E., Lobb, R.R. Cell (1990) [Pubmed]
  9. Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Holzmann, B., McIntyre, B.W., Weissman, I.L. Cell (1989) [Pubmed]
  10. Alpha4beta1 integrin affinity changes govern cell adhesion. Chigaev, A., Zwartz, G., Graves, S.W., Dwyer, D.C., Tsuji, H., Foutz, T.D., Edwards, B.S., Prossnitz, E.R., Larson, R.S., Sklar, L.A. J. Biol. Chem. (2003) [Pubmed]
  11. Real time analysis of the affinity regulation of alpha 4-integrin. The physiologically activated receptor is intermediate in affinity between resting and Mn(2+) or antibody activation. Chigaev, A., Blenc, A.M., Braaten, J.V., Kumaraswamy, N., Kepley, C.L., Andrews, R.P., Oliver, J.M., Edwards, B.S., Prossnitz, E.R., Larson, R.S., Sklar, L.A. J. Biol. Chem. (2001) [Pubmed]
  12. Regulation of cell adhesion by affinity and conformational unbending of alpha4beta1 integrin. Chigaev, A., Waller, A., Zwartz, G.J., Buranda, T., Sklar, L.A. J. Immunol. (2007) [Pubmed]
  13. CD49d expression and function on allergen-stimulated T cells from blood and airway. Pacheco, K.A., Tarkowski, M., Klemm, J., Rosenwasser, L.J. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  14. Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. Henderson, W.R., Chi, E.Y., Albert, R.K., Chu, S.J., Lamm, W.J., Rochon, Y., Jonas, M., Christie, P.E., Harlan, J.M. J. Clin. Invest. (1997) [Pubmed]
  15. Real-time analysis of very late antigen-4 affinity modulation by shear. Zwartz, G.J., Chigaev, A., Dwyer, D.C., Foutz, T.D., Edwards, B.S., Sklar, L.A. J. Biol. Chem. (2004) [Pubmed]
  16. The expression of integrins on activated T-cells in multiple sclerosis. Effect of intravenous methylprednisolone treatment. Luján, S., Masjuan, J., Roldán, E., Villar, L.M., González-Porqué, P., Alvarez-Cermeño, J.C. Mult. Scler. (1998) [Pubmed]
  17. Effect of cysteine protease of Porphyromonas gingivalis on adhesion molecules in gingival epithelial cells. Wang, P.L., Shinohara, M., Murakawa, N., Endo, M., Sakata, S., Okamura, M., Ohura, K. Jpn. J. Pharmacol. (1999) [Pubmed]
  18. Assignment of three rat integrin genes to chromosome 19 (ITGB1), chromosome 3 (ITGA4), and chromosome 7 (ITGA5). Szpirer, C., Rivière, M., Szpirer, J., Levan, G., Jaspers, M., Vekemans, S., Cassiman, J.J. Mamm. Genome (1992) [Pubmed]
  19. Lymphocyte adhesion through very late antigen 4: evidence for a novel binding site in the alternatively spliced domain of vascular cell adhesion molecule 1 and an additional alpha 4 integrin counter-receptor on stimulated endothelium. Vonderheide, R.H., Springer, T.A. J. Exp. Med. (1992) [Pubmed]
  20. An alternative leukocyte homotypic adhesion mechanism, LFA-1/ICAM-1-independent, triggered through the human VLA-4 integrin. Campanero, M.R., Pulido, R., Ursa, M.A., Rodríguez-Moya, M., de Landázuri, M.O., Sánchez-Madrid, F. J. Cell Biol. (1990) [Pubmed]
  21. Sequential regulation of alpha 4 beta 1 and alpha 5 beta 1 integrin avidity by CC chemokines in monocytes: implications for transendothelial chemotaxis. Weber, C., Alon, R., Moser, B., Springer, T.A. J. Cell Biol. (1996) [Pubmed]
  22. Freezing adhesion molecules in a state of high-avidity binding blocks eosinophil migration. Kuijpers, T.W., Mul, E.P., Blom, M., Kovach, N.L., Gaeta, F.C., Tollefson, V., Elices, M.J., Harlan, J.M. J. Exp. Med. (1993) [Pubmed]
  23. Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1. van Seventer, G.A., Newman, W., Shimizu, Y., Nutman, T.B., Tanaka, Y., Horgan, K.J., Gopal, T.V., Ennis, E., O'Sullivan, D., Grey, H. J. Exp. Med. (1991) [Pubmed]
  24. Phenotypic and functional changes in peripheral blood monocytes during progression of human immunodeficiency virus infection. Effects of soluble immune complexes, cytokines, subcellular particulates from apoptotic cells, and HIV-1-encoded proteins on monocytes phagocytic function, oxidative burst, transendothelial migration, and cell surface phenotype. Trial, J., Birdsall, H.H., Hallum, J.A., Crane, M.L., Rodriguez-Barradas, M.C., de Jong, A.L., Krishnan, B., Lacke, C.E., Figdor, C.G., Rossen, R.D. J. Clin. Invest. (1995) [Pubmed]
  25. Conformational mAb as a tool for integrin ligand discovery. Njus, B.H., Chigaev, A., Waller, A., Wlodek, D., Ostopovici-Halip, L., Ursu, O., Wang, W., Oprea, T.I., Bologa, C.G., Sklar, L.A. Assay. Drug. Dev. Technol. (2009) [Pubmed]
  26. Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin conformational regulation. Chigaev, A., Waller, A., Amit, O., Halip, L., Bologa, C.G., Sklar, L.A. J. Biol. Chem. (2009) [Pubmed]
  27. Stimulation of human bone marrow stromal cell tyrosine kinases and IL-6 production by contact with B lymphocytes. Jarvis, L.J., LeBien, T.W. J. Immunol. (1995) [Pubmed]
  28. Stimulation of Human Endothelium with IL-3 Induces Selective Basophil Accumulation In Vitro. Lim, L.H., Burdick, M.M., Hudson, S.A., Mustafa, F.B., Konstantopoulos, K., Bochner, B.S. J. Immunol. (2006) [Pubmed]
  29. Effects of integrin clustering on human lung mast cells and basophils. Lavens, S.E., Goldring, K., Thomas, L.H., Warner, J.A. Am. J. Respir. Cell Mol. Biol. (1996) [Pubmed]
  30. Arrangement of domains, and amino acid residues required for binding of vascular cell adhesion molecule-1 to its counter-receptor VLA-4 (alpha 4 beta 1). Osborn, L., Vassallo, C., Browning, B.G., Tizard, R., Haskard, D.O., Benjamin, C.D., Dougas, I., Kirchhausen, T. J. Cell Biol. (1994) [Pubmed]
  31. beta1-Integrins dominate cell traffic of leukemic cells in human bone-marrow stroma. Van der Velde-Zimmerman, D., Smits, A.J., Verdaasdonk, M.A., Rademakers, L.H., Werner, N., Spierings, D.C., De Weger, R.A., Van den Tweel, J.G., Joling, P. Int. J. Cancer (1996) [Pubmed]
  32. The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion. Siegelman, M.H., Stanescu, D., Estess, P. J. Clin. Invest. (2000) [Pubmed]
  33. Differential expression of VLA-4 integrin by resident and peripheral blood B lymphocytes. Acquisition of functionally active alpha 4 beta 1-fibronectin receptors upon B cell activation. Postigo, A.A., Pulido, R., Campanero, M.R., Acevedo, A., García-Pardo, A., Corbi, A.L., Sanchez-Madrid, F., De Landazuri, M.O. Eur. J. Immunol. (1991) [Pubmed]
  34. Interferon-beta-1a induces increases in vascular cell adhesion molecule: implications for its mode of action in multiple sclerosis. Graber, J., Zhan, M., Ford, D., Kursch, F., Francis, G., Bever, C., Panitch, H., Calabresi, P.A., Dhib-Jalbut, S. J. Neuroimmunol. (2005) [Pubmed]
  35. VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses. Mittelbrunn, M., Molina, A., Escribese, M.M., Yáñez-Mó, M., Escudero, E., Ursa, A., Tejedor, R., Mampaso, F., Sánchez-Madrid, F. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  36. Galphas-coupled receptor signaling actively down-regulates alpha4beta1-integrin affinity: a possible mechanism for cell de-adhesion. Chigaev, A., Waller, A., Amit, O., Sklar, L.A. BMC. Immunol. (2008) [Pubmed]
  37. 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). Shang, X.Z., Lang, B.J., Issekutz, A.C. J. Immunol. (1998) [Pubmed]
  38. Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. Davis, L.S., Oppenheimer-Marks, N., Bednarczyk, J.L., McIntyre, B.W., Lipsky, P.E. J. Immunol. (1990) [Pubmed]
  39. VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine production by synovial nurse-like cells from rheumatoid arthritis patients. Takeuchi, E., Tanaka, T., Umemoto, E., Tomita, T., Shi, K., Takahi, K., Suzuki, R., Ochi, T., Miyasaka, M. Arthritis Res. (2002) [Pubmed]
  40. A monoclonal antibody to beta 1 integrin (CD29) stimulates VLA-dependent adherence of leukocytes to human umbilical vein endothelial cells and matrix components. Kovach, N.L., Carlos, T.M., Yee, E., Harlan, J.M. J. Cell Biol. (1992) [Pubmed]
  41. Human monocytes bind to two cytokine-induced adhesive ligands on cultured human endothelial cells: endothelial-leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1. Carlos, T., Kovach, N., Schwartz, B., Rosa, M., Newman, B., Wayner, E., Benjamin, C., Osborn, L., Lobb, R., Harlan, J. Blood (1991) [Pubmed]
  42. Effect of interleukin-5 exposure during in vitro eosinophilopiesis on MAC-1 adhesion molecule expression and function on cultured human eosinophils. Hamann, K.J., Neeley, S.P., Dowling, T.L., Grant, J.A., Leff, A.R. Blood (1996) [Pubmed]
  43. Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. Correlation with distinct alpha 4 epitopes. Pulido, R., Elices, M.J., Campanero, M.R., Osborn, L., Schiffer, S., García-Pardo, A., Lobb, R., Hemler, M.E., Sánchez-Madrid, F. J. Biol. Chem. (1991) [Pubmed]
  44. Adhesion molecules on peripheral blood-derived CD34+ cells: effects of cryopreservation and short-term ex vivo incubation with serum and cytokines. Koenigsmann, M.P., Koenigsmann, M., Notter, M., Neuloh, M., Mücke, C., Thiel, E., Berdel, W.E. Bone Marrow Transplant. (1998) [Pubmed]
  45. Expression of adhesion molecules and effect of disodium cromoglycate treatment in asthmatics. Jahnová, E., Horváthová, M., Gazdík, F. Physiological research / Academia Scientiarum Bohemoslovaca. (1998) [Pubmed]
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