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Gene Review

IGBP1  -  immunoglobulin (CD79A) binding protein 1

Homo sapiens

Synonyms: ALPHA-4, B-cell signal transduction molecule alpha 4, CD79a-binding protein 1, IBP1, Immunoglobulin-binding protein 1, ...
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Disease relevance of IGBP1

  • A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13 [1].
  • The alpha promoter regulator-ovalbumin chimeric gene resident in human cells is regulated like the authentic alpha 4 gene after infection with herpes simplex virus 1 mutants in alpha 4 gene [2].
  • Aerobic anoxygenic phototrophic bacteria are classified in two marine (Erythrobacter and Roseobacter) and six freshwater (Acidiphilium, Erythromicrobium, Erythromonas, Porphyrobacter, Roseococcus, and Sandaracinobacter) genera, which phylogenetically belong to the alpha-1, alpha-3, and alpha-4 subclasses of the class Proteobacteria [3].
  • In brain the alpha 5 gene product is present both in alpha 3- and in alpha 4-based receptor subtypes, while in the ganglion it is found in an alpha 3-based receptor subtype concentrated in postsynaptic membrane [4].
  • Analysis of the functional epitopes on the alpha 4 chain demonstrated that antigen densities of all the functional epitopes were increased in those with vasculitis, indicating that the increased expression of VLA-4 resulted from the increased number of VLA-4 molecules, and was not secondary to an increase in one particular functional epitope [5].

Psychiatry related information on IGBP1


High impact information on IGBP1

  • The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex [11].
  • A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy [11].
  • MAdCAM-1 is also a ligand for the lymphocyte integrin homing receptor for Peyer's patches, alpha 4 beta 7 (ref. 7), and may be uniquely adapted to support both selectin-mediated lymphocyte rolling and integrin-mediated adhesion and arrest in vivo [12].
  • The peptide alpha 4 is a designed four-helix bundle that contains a highly simplified hydrophobic core composed exclusively of leucine residues; its tertiary structure is therefore largely dictated by hydrophobic forces [13].
  • Major advances in the leukocyte integrin field this year have been the realization of the extensive roles for alpha 4 integrins in leukocyte function, the solution of the crystal structure of an I domain and its identification as a major ligand-binding site, and the initial understanding of how divalent cations may function in an active integrin [14].

Chemical compound and disease context of IGBP1


Biological context of IGBP1

  • CONCLUSIONS: Our findings not only implicate Alpha 4 in the pathogenesis of Opitz GBBB syndrome but also support our earlier hypothesis that MID2 is a modifier of the X-linked phenotype [20].
  • One of these is likely to provide the binding interface for Alpha 4 that is required for the localized turnover of the catalytic subunit of PP2A, the major Ser/Thr phosphatase [21].
  • Contiguous localization of the genes encoding human insulin-like growth factor binding proteins 1 (IGBP1) and 3 (IGBP3) on chromosome 7 [22].
  • Further characterization of the IGBP1 DNA sequence disclosed a duplication of the intron 3-exon 4 junction within the third intron [22].
  • Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4 [23].

Anatomical context of IGBP1


Associations of IGBP1 with chemical compounds

  • The disabling H118N mutation at the active site or the presence of the active site inhibitor microcystin-LR did not interfere with binding of PP2Ac to either the A subunit or alpha-4, showing that these are allosteric regulators [28].
  • The increase in tyrosine phosphorylation of pp105 was specifically mediated by VLA-4, since mAbs against alpha 4, but not against other VLA alpha chains, could induce this phosphorylation [29].
  • Parts of the alpha 4 sequence most conserved in other alpha chains include (i) the positions of 19/24 cysteine residues, (ii) three potential divalent cation binding sites of the general structure DXDXDGXXD and (iii) the transmembrane region [30].
  • Here, we identified critical residues of alpha 4 for ligand binding using alanine-scanning mutagenesis of the previously localized putative ligand binding sites (residues 108-268) [31].
  • In conclusion, these findings show clearly that cultured T lymphocytes use two independent receptors during attachment to fibronectin and that (a) alpha 5 beta 1 is the receptor for the RGD containing cell adhesion domain, and (b) alpha 4 beta 1 is the receptor for a carboxy-terminal cell adhesion region containing the Heparin II and IIICS domains [32].

Physical interactions of IGBP1

  • These alpha 4 beta 7-positive JY cells bound poorly or not at all to VLA-4 ligands (soluble form of vascular cell adhesion molecule 1 (sVCAM-1) and the CS1 region of fibronectin) [33].
  • To localize the potential alpha 4 beta 1-binding site within the TSP-1 molecule, the protein was subjected to limited proteolysis with chymotrypsin in the absence of calcium [34].
  • The presence of complex N-linked oligosaccharides did not seem to be necessary for alpha 4 cleavage or for binding of the alpha 4 beta 1 complex to a synthetic peptide corresponding to the binding site for this receptor on fibronectin [35].
  • Our results suggest a model where VCAM-1 would initially participate in the retention of T cells to the endothelium by binding alpha 4 beta 1 integrin [36].
  • A fragment of paxillin binds the alpha 4 integrin cytoplasmic domain (tail) and selectively inhibits alpha 4-mediated cell migration [37].

Enzymatic interactions of IGBP1


Co-localisations of IGBP1


Regulatory relationships of IGBP1


Other interactions of IGBP1

  • Overlap in the clinical features of FG and Opitz GBBB syndromes warrants investigation of Alpha 4 as a candidate for causing FG syndrome [20].
  • Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome [1].
  • Adhesion of CFC seen after interferon-alpha treatment could be inhibited by blocking antibodies directed at the alpha 4, alpha 5, and beta 1 integrins and vascular cell adhesion molecule, but not CD44 or intracellular adhesion molecule, suggesting that interferon-alpha induces normalization of progenitor-stroma interactions in CML [45].
  • In contrast to mAbs directed to VLA-4 alpha-subunit (alpha 4, CD49d), mAb 8A2 did not induce homotypic aggregation of PBL [46].
  • Loss of adhesion to FN was correlated with the concomitant decrease in the expression of alpha 4 and alpha 5 integrin subunits [47].

Analytical, diagnostic and therapeutic context of IGBP1


  1. A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13. Graham, J.M., Wheeler, P., Tackels-Horne, D., Lin, A.E., Hall, B.D., May, M., Short, K.M., Schwartz, C.E., Cox, T.C. Am. J. Med. Genet. A (2003) [Pubmed]
  2. The alpha promoter regulator-ovalbumin chimeric gene resident in human cells is regulated like the authentic alpha 4 gene after infection with herpes simplex virus 1 mutants in alpha 4 gene. Herz, C., Roizman, B. Cell (1983) [Pubmed]
  3. Aerobic anoxygenic phototrophic bacteria. Yurkov, V.V., Beatty, J.T. Microbiol. Mol. Biol. Rev. (1998) [Pubmed]
  4. The alpha 5 gene product assembles with multiple acetylcholine receptor subunits to form distinctive receptor subtypes in brain. Conroy, W.G., Vernallis, A.B., Berg, D.K. Neuron (1992) [Pubmed]
  5. Upregulated expression and function of integrin adhesive receptors in systemic lupus erythematosus patients with vasculitis. Takeuchi, T., Amano, K., Sekine, H., Koide, J., Abe, T. J. Clin. Invest. (1993) [Pubmed]
  6. Mutational analysis of the nicotinic acetylcholine receptor alpha 4 subunit gene in attention deficit/hyperactivity disorder: evidence for association of an intronic polymorphism with attention problems. Todd, R.D., Lobos, E.A., Sun, L.W., Neuman, R.J. Mol. Psychiatry (2003) [Pubmed]
  7. Nicotinic receptor subtypes and cognitive function. Levin, E.D. J. Neurobiol. (2002) [Pubmed]
  8. Epibatidine and ABT 418 reveal selective losses of alpha 4 beta 2 nicotinic receptors in Alzheimer brains. Warpman, U., Nordberg, A. Neuroreport (1995) [Pubmed]
  9. Appearance of localized immunoreactivity for the alpha 4 integrin subunit and for fibronectin in brains from Alzheimer's, Lewy body dementia patients and aged controls. Van Gool, D., Carmeliet, G., Triau, E., Cassiman, J.J., Dom, R. Neurosci. Lett. (1994) [Pubmed]
  10. Neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and panic disorder: an association study. Steinlein, O.K., Deckert, J., Nöthen, M.M., Franke, P., Maier, W., Beckmann, H., Propping, P. Am. J. Med. Genet. (1997) [Pubmed]
  11. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Steinlein, O.K., Mulley, J.C., Propping, P., Wallace, R.H., Phillips, H.A., Sutherland, G.R., Scheffer, I.E., Berkovic, S.F. Nat. Genet. (1995) [Pubmed]
  12. L-selectin-mediated lymphocyte rolling on MAdCAM-1. Berg, E.L., McEvoy, L.M., Berlin, C., Bargatze, R.F., Butcher, E.C. Nature (1993) [Pubmed]
  13. Metal ion-dependent modulation of the dynamics of a designed protein. Handel, T.M., Williams, S.A., DeGrado, W.F. Science (1993) [Pubmed]
  14. Leukocyte integrins. Stewart, M., Thiel, M., Hogg, N. Curr. Opin. Cell Biol. (1995) [Pubmed]
  15. Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a gut-homing integrin alpha 4 beta 7. Hesterberg, P.E., Winsor-Hines, D., Briskin, M.J., Soler-Ferran, D., Merrill, C., Mackay, C.R., Newman, W., Ringler, D.J. Gastroenterology (1996) [Pubmed]
  16. Coordinate role for cell surface chondroitin sulfate proteoglycan and alpha 4 beta 1 integrin in mediating melanoma cell adhesion to fibronectin. Iida, J., Skubitz, A.P., Furcht, L.T., Wayner, E.A., McCarthy, J.B. J. Cell Biol. (1992) [Pubmed]
  17. Herpes simplex virus protein kinase US3 activates and functionally overlaps protein kinase A to block apoptosis. Benetti, L., Roizman, B. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. Thiol/disulfide formation associated with the redox activity of the [Fe3S4] cluster of Desulfovibrio gigas ferredoxin II. 1H NMR and Mössbauer spectroscopic study. Macedo, A.L., Moura, I., Surerus, K.K., Papaefthymiou, V., Liu, M.Y., LeGall, J., Münck, E., Moura, J.J. J. Biol. Chem. (1994) [Pubmed]
  19. The novel recognition site in the C-terminal heparin-binding domain of fibronectin by integrin alpha 4 beta 1 receptor on HL-60 cells. Mohri, H., Katoh, K., Iwamatsu, A., Okubo, T. Exp. Cell Res. (1996) [Pubmed]
  20. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. Short, K.M., Hopwood, B., Yi, Z., Cox, T.C. BMC Cell Biol. (2002) [Pubmed]
  21. Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING. Massiah, M.A., Simmons, B.N., Short, K.M., Cox, T.C. J. Mol. Biol. (2006) [Pubmed]
  22. Contiguous localization of the genes encoding human insulin-like growth factor binding proteins 1 (IGBP1) and 3 (IGBP3) on chromosome 7. Ehrenborg, E., Larsson, C., Stern, I., Janson, M., Powell, D.R., Luthman, H. Genomics (1992) [Pubmed]
  23. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Liu, J., Prickett, T.D., Elliott, E., Meroni, G., Brautigan, D.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Expression and chromosomal localization of the human alpha 4/IGBP1 gene, the structure of which is closely related to the yeast TAP42 protein of the rapamycin-sensitive signal transduction pathway. Onda, M., Inui, S., Maeda, K., Suzuki, M., Takahashi, E., Sakaguchi, N. Genomics (1997) [Pubmed]
  25. Interchangeable alpha chain cytoplasmic domains play a positive role in control of cell adhesion mediated by VLA-4, a beta 1 integrin. Kassner, P.D., Hemler, M.E. J. Exp. Med. (1993) [Pubmed]
  26. 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]
  27. Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms. Salmi, M., Andrew, D.P., Butcher, E.C., Jalkanen, S. J. Exp. Med. (1995) [Pubmed]
  28. Overlapping binding sites in protein phosphatase 2A for association with regulatory A and alpha-4 (mTap42) subunits. Prickett, T.D., Brautigan, D.L. J. Biol. Chem. (2004) [Pubmed]
  29. Ligation of VLA-4 on T cells stimulates tyrosine phosphorylation of a 105-kD protein. Nojima, Y., Rothstein, D.M., Sugita, K., Schlossman, S.F., Morimoto, C. J. Exp. Med. (1992) [Pubmed]
  30. The primary structure of the alpha 4 subunit of VLA-4: homology to other integrins and a possible cell-cell adhesion function. Takada, Y., Elices, M.J., Crouse, C., Hemler, M.E. EMBO J. (1989) [Pubmed]
  31. Critical amino acid residues for ligand binding are clustered in a predicted beta-turn of the third N-terminal repeat in the integrin alpha 4 and alpha 5 subunits. Irie, A., Kamata, T., Puzon-McLaughlin, W., Takada, Y. EMBO J. (1995) [Pubmed]
  32. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. Wayner, E.A., Garcia-Pardo, A., Humphries, M.J., McDonald, J.A., Carter, W.G. J. Cell Biol. (1989) [Pubmed]
  33. Adhesion to vascular cell adhesion molecule 1 and fibronectin. Comparison of alpha 4 beta 1 (VLA-4) and alpha 4 beta 7 on the human B cell line JY. Chan, B.M., Elices, M.J., Murphy, E., Hemler, M.E. J. Biol. Chem. (1992) [Pubmed]
  34. Adhesion of osteosarcoma cells to the 70-kDa core region of thrombospondin-1 is mediated by the alpha 4 beta 1 integrin. Decker, S., van Valen, F., Vischer, P. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  35. Post-translational processing of the leukocyte integrin alpha 4 beta 1. Bednarczyk, J.L., Szabo, M.C., McIntyre, B.W. J. Biol. Chem. (1992) [Pubmed]
  36. VCAM-1 is internalized by a clathrin-related pathway in human endothelial cells but its alpha 4 beta 1 integrin counter-receptor remains associated with the plasma membrane in human T lymphocytes. Ricard, I., Payet, M.D., Dupuis, G. Eur. J. Immunol. (1998) [Pubmed]
  37. A fragment of paxillin binds the alpha 4 integrin cytoplasmic domain (tail) and selectively inhibits alpha 4-mediated cell migration. Liu, S., Kiosses, W.B., Rose, D.M., Slepak, M., Salgia, R., Griffin, J.D., Turner, C.E., Schwartz, M.A., Ginsberg, M.H. J. Biol. Chem. (2002) [Pubmed]
  38. Focal adhesion kinase (pp125FAK) is tyrosine phosphorylated after engagement of alpha 4 beta 1 and alpha 5 beta 1 integrins on human T-lymphoblastic cells. Nojima, Y., Tachibana, K., Sato, T., Schlossman, S.F., Morimoto, C. Cell. Immunol. (1995) [Pubmed]
  39. Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). Mannion, B.A., Berditchevski, F., Kraeft, S.K., Chen, L.B., Hemler, M.E. J. Immunol. (1996) [Pubmed]
  40. Co-clustering of beta 1 integrins, cytoskeletal proteins, and tyrosine-phosphorylated substrates during integrin-mediated leukocyte aggregation. Sánchez-Mateos, P., Campanero, M.R., Balboa, M.A., Sánchez-Madrid, F. J. Immunol. (1993) [Pubmed]
  41. Mutation of Tyr307 and Leu309 in the protein phosphatase 2A catalytic subunit favors association with the alpha 4 subunit which promotes dephosphorylation of elongation factor-2. Chung, H., Nairn, A.C., Murata, K., Brautigan, D.L. Biochemistry (1999) [Pubmed]
  42. Counter-receptors on human basophils for endothelial cell adhesion molecules. Bochner, B.S., Sterbinsky, S.A., Briskin, M., Saini, S.S., MacGlashan, D.W. J. Immunol. (1996) [Pubmed]
  43. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. Jiang, Y., Beller, D.I., Frendl, G., Graves, D.T. J. Immunol. (1992) [Pubmed]
  44. VLA-4 integrin can mediate CD11/CD18-independent transendothelial migration of human monocytes. Chuluyan, H.E., Issekutz, A.C. J. Clin. Invest. (1993) [Pubmed]
  45. Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function. Bhatia, R., Wayner, E.A., McGlave, P.B., Verfaillie, C.M. J. Clin. Invest. (1994) [Pubmed]
  46. 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]
  47. IFN-gamma and transforming growth factor-beta 1 differently regulate fibronectin and laminin receptors of human differentiating monocytic cells. Bauvois, B., Rouillard, D., Sanceau, J., Wietzerbin, J. J. Immunol. (1992) [Pubmed]
  48. Evidence for a role of the integrin VLA-4 in lympho-hemopoiesis. Miyake, K., Weissman, I.L., Greenberger, J.S., Kincade, P.W. J. Exp. Med. (1991) [Pubmed]
  49. Differential expression of tissue-specific adhesion molecules on human circulating antibody-forming cells after systemic, enteric, and nasal immunizations. A molecular basis for the compartmentalization of effector B cell responses. Quiding-Järbrink, M., Nordström, I., Granström, G., Kilander, A., Jertborn, M., Butcher, E.C., Lazarovits, A.I., Holmgren, J., Czerkinsky, C. J. Clin. Invest. (1997) [Pubmed]
  50. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. Rüegg, C., Postigo, A.A., Sikorski, E.E., Butcher, E.C., Pytela, R., Erle, D.J. J. Cell Biol. (1992) [Pubmed]
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