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Gene Review

TUBB4A  -  tubulin, beta 4A class IVa

Homo sapiens

Synonyms: DYT4, TUBB4, TUBB5, Tubulin 5 beta, Tubulin beta-4 chain, ...
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Disease relevance of TUBB4

  • Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment [1].
  • Here we introduce an approach based on phage display technology to identify molecules that specifically interact with the cytoplasmic domain of the beta 5 integrin subunit [2].
  • M21 human melanoma cells and H2981 lung carcinoma cells use both alpha v-containing integrins in adhering to vitronectin while UCLA-P3 lung carcinoma cells adhere exclusively with alpha v beta 5 [3].
  • Integrin alpha v beta 3 is able to induce cell spreading, migration, angiogenesis, and tumor metastasis without additional stimulators, whereas alpha v beta 5 requires exogenous activation of protein kinase C (PKC) to mediate these processes [4].
  • These studies provide evidence for the involvement of a cellular receptor in virus-mediated membrane permeabilization and suggest a novel biological role for integrin alpha v beta 5 in the infectious pathway of a human adenovirus [5].

High impact information on TUBB4

  • Viral overlay experiments on purified plasma membrane proteins as well as immunoprecipitated integrin beta5 subunit demonstrated that AAV directly associates with the beta5 subunit of alphaVbeta5 integrin [6].
  • Alpha v beta 5 integrin-dependent programmed cell death triggered by a peptide mimic of annexin V [2].
  • We show that a peptide selected for binding specifically to the beta 5 cytoplasmic domain (VVISYSMPD) induces apoptosis upon internalization [2].
  • The cell death process induced by VVISYSMPD is sensitive to modulation by growth factors and by protein kinase C (PKC), and it cannot be triggered in beta 5 null cells [2].
  • Transfection experiments showed that the substitution of beta5i (LMP7) for beta5 is necessary and sufficient for producing the peptide, whereas a mutated form of beta5i (LMP7) lacking the catalytically active site was ineffective [7].

Chemical compound and disease context of TUBB4


Biological context of TUBB4


Anatomical context of TUBB4

  • RESULTS: Integrin PCR products corresponding to the beta1-, beta4-, beta5-, and beta8-integrin subunits and the alpha-integrin subunits, alpha1-6-, alpha9-11- and alphav-integrin were identified in the sclera and in scleral fibroblast cultures [13].
  • This approach allowed us to identify three amino acid residues in the extreme COOH terminus of these toxins that are largely responsible for their ability to stimulate either human V beta 5- or V beta 8-bearing T cells, or mouse V beta 3 or V beta 11 [14].
  • By immunoprecipitation, beta 5 was most prevalent on carcinoma cell lines, was also present on hepatoma and fibroblast cell lines, and was absent from lymphoblastoid cells and platelets [15].
  • Conversely, the alpha v integrin subunit, presumably in association with beta 5, was expressed at the basal surface in growing and migrating but not in stationary keratinocytes [16].
  • The beta 5 cDNA was isolated from a human thymic epithelial cell library, using oligonucleotide probes that were designed from a region highly conserved among the known beta 1, beta 2 and beta 3 sequences [15].

Associations of TUBB4 with chemical compounds

  • We demonstrate that the vitro-nectin-binding integrins alpha v beta 3 and alpha v beta 5 promote viral infection in a novel way since antibodies against these receptors or soluble penton base block virus internalization without affecting attachment [1].
  • Two novel human glycoprotein hormonelike genes, alpha2 (A2) and beta5 (B5), recently have been identified [17].
  • Protein kinase C (PKC) activation also leads to alpha v beta 5-directed motility on vitronectin; however, this is not blocked by tyrosine kinase inhibitors [18].
  • The alpha v beta 5 interaction with these peptides was not solely due to high content of basic amino acids in the ligand sequences; alpha v beta 5 did not bind substantially to peptides consisting entirely of arginine or lysine, whereas a beta 1 integrin did bind to these peptides [19].
  • This article reports that IVIg contains antibodies to the Arg-Gly-Asp (RGD) sequence, and the attachment site of a number of adhesive extracellular matrix proteins, including ligands for beta1, beta3, and beta5 integrins [20].

Physical interactions of TUBB4

  • Deletion of the ERK2 binding site on the beta6 cytoplasmic domain inhibits tumour growth and leads to an association between ERK and the beta5 subunit [21].
  • We show for the first time in protozoa that beta-tubulin folding is assisted by CCT and requires cofactor A. In addition, we observed that E. focardiibeta-T1 competes with human beta5 tubulin isotype for binding to CCT [22].
  • After Csk induction, the cells became spherical and more loosely attached to the culture substratum, and the alpha v beta 5 integrin complex (vitronectin receptor) of focal adhesions was redistributed to a novel type of structure consisting of punctate plaques on the ventral cell surface [23].
  • Similarly, antibodies that bind beta 3 proximal to the ligand-binding site failed to react with beta 5, indicating an architectural difference at the ligand-binding site of these related integrins [24].
  • CK2alpha monomers with this closed beta4/beta5 loop conformation are unable to bind CK2beta dimers in the common way for sterical reasons, suggesting a mechanism to protect CK2alpha from integration into CK2 holoenzyme complexes [25].

Regulatory relationships of TUBB4

  • We conclude that PKC regulates localization of cytoskeletal proteins and phosphorylation of FAK induced by alpha v beta 5 [4].
  • By contrast, beta5-containing dimers inhibited GIRK channel currents [26].
  • Specifically, monoclonal antibodies directed to functional epitopes on both receptors were required to block adhesion of M21 or H2981 cells while adhesion of UCLA-P3 cells to vitronectin could be blocked with a monoclonal antibody to alpha v beta 5 [3].
  • The beta5 gamma2HF dimer activated phospholipase C-beta with a potency and efficacy similar to that of beta1 gamma2 or beta1 gamma2HF; however, it was markedly less effective than the beta1 gamma2HF or beta1 gamma2 dimer in its ability to activate type II adenylyl cyclase (EC50 of approximately 700 nM versus 25 nM) [27].
  • In T47D cells estradiol caused a 6-fold up-regulation of total ER-beta, and modified the relative expression pattern of the various isoforms, up-regulating the beta2 and down-regulating the beta5 isoform [28].

Other interactions of TUBB4

  • For this equilibrium shift, a C-helix repositioning around the C-helix residues Thr-127 and Ser-128 has been reported as a critical local event along with proper beta4/beta5 positioning [29].
  • Functionally, PAK4 induced integrin alpha v beta 5-mediated, but not beta1-mediated, human breast carcinoma cell migration, while no changes in integrin cell surface expression levels were observed [30].
  • We report here that epidermal growth factor receptor (EGFR) activation leads to de novo alpha v beta 5-dependent FG cell migration on vitronectin [18].
  • In contrast to yeast, the presence of the beta 5 propeptide is not essential for incorporation of LMP7 into the proteasome complex [31].
  • Patient PBL contained mature T cells (CD3+ TCR alpha beta+) of the CD4 and CD8 subset, showing an apparently normal TCR diversity, as judged by use of anti-V beta 5, -V beta 6, -V beta 8, -V beta 12, and -V alpha 2 mAb [32].

Analytical, diagnostic and therapeutic context of TUBB4


  1. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Wickham, T.J., Mathias, P., Cheresh, D.A., Nemerow, G.R. Cell (1993) [Pubmed]
  2. Alpha v beta 5 integrin-dependent programmed cell death triggered by a peptide mimic of annexin V. Cardó-Vila, M., Arap, W., Pasqualini, R. Mol. Cell (2003) [Pubmed]
  3. Integrins alpha v beta 3 and alpha v beta 5 contribute to cell attachment to vitronectin but differentially distribute on the cell surface. Wayner, E.A., Orlando, R.A., Cheresh, D.A. J. Cell Biol. (1991) [Pubmed]
  4. Protein kinase C regulates alpha v beta 5-dependent cytoskeletal associations and focal adhesion kinase phosphorylation. Lewis, J.M., Cheresh, D.A., Schwartz, M.A. J. Cell Biol. (1996) [Pubmed]
  5. Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. Wickham, T.J., Filardo, E.J., Cheresh, D.A., Nemerow, G.R. J. Cell Biol. (1994) [Pubmed]
  6. AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Summerford, C., Bartlett, J.S., Samulski, R.J. Nat. Med. (1999) [Pubmed]
  7. The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome. Schultz, E.S., Chapiro, J., Lurquin, C., Claverol, S., Burlet-Schiltz, O., Warnier, G., Russo, V., Morel, S., Lévy, F., Boon, T., Van den Eynde, B.J., van der Bruggen, P. J. Exp. Med. (2002) [Pubmed]
  8. Vitronectin expression in differentiating neuroblastic tumors: integrin alpha v beta 5 mediates vitronectin-dependent adhesion of retinoic-acid-differentiated neuroblastoma cells. Gladson, C.L., Dennis, C., Rotolo, T.C., Kelly, D.R., Grammer, J.R. Am. J. Pathol. (1997) [Pubmed]
  9. Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells. Kraus, M., R??ckrich, T., Reich, M., Gogel, J., Beck, A., Kammer, W., Berkers, C.R., Burg, D., Overkleeft, H., Ovaa, H., Driessen, C. Leukemia (2007) [Pubmed]
  10. Effects of phospholipid unsaturation on the bilayer nonpolar region: a molecular simulation study. Róg, T., Murzyn, K., Gurbiel, R., Takaoka, Y., Kusumi, A., Pasenkiewicz-Gierula, M. J. Lipid Res. (2004) [Pubmed]
  11. Contrasting roles for integrin beta 1 and beta 5 cytoplasmic domains in subcellular localization, cell proliferation, and cell migration. Pasqualini, R., Hemler, M.E. J. Cell Biol. (1994) [Pubmed]
  12. Switch from alphavbeta5 to alphavbeta6 integrin expression protects squamous cell carcinomas from anoikis. Janes, S.M., Watt, F.M. J. Cell Biol. (2004) [Pubmed]
  13. Characterization of the integrin receptor subunit profile in the mammalian sclera. Metlapally, R., Jobling, A.I., Gentle, A., McBrien, N.A. Mol. Vis. (2006) [Pubmed]
  14. Localization of a site on bacterial superantigens that determines T cell receptor beta chain specificity. Mollick, J.A., McMasters, R.L., Grossman, D., Rich, R.R. J. Exp. Med. (1993) [Pubmed]
  15. Cloning, primary structure and properties of a novel human integrin beta subunit. Ramaswamy, H., Hemler, M.E. EMBO J. (1990) [Pubmed]
  16. Polarized expression of integrin receptors (alpha 6 beta 4, alpha 2 beta 1, alpha 3 beta 1, and alpha v beta 5) and their relationship with the cytoskeleton and basement membrane matrix in cultured human keratinocytes. Marchisio, P.C., Bondanza, S., Cremona, O., Cancedda, R., De Luca, M. J. Cell Biol. (1991) [Pubmed]
  17. Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor. Nakabayashi, K., Matsumi, H., Bhalla, A., Bae, J., Mosselman, S., Hsu, S.Y., Hsueh, A.J. J. Clin. Invest. (2002) [Pubmed]
  18. Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin. Klemke, R.L., Yebra, M., Bayna, E.M., Cheresh, D.A. J. Cell Biol. (1994) [Pubmed]
  19. A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin. Vogel, B.E., Lee, S.J., Hildebrand, A., Craig, W., Pierschbacher, M.D., Wong-Staal, F., Ruoslahti, E. J. Cell Biol. (1993) [Pubmed]
  20. Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Vassilev, T.L., Kazatchkine, M.D., Van Huyen, J.P., Mekrache, M., Bonnin, E., Mani, J.C., Lecroubier, C., Korinth, D., Baruch, D., Schriever, F., Kaveri, S.V. Blood (1999) [Pubmed]
  21. Direct integrin alphavbeta6-ERK binding: implications for tumour growth. Ahmed, N., Niu, J., Dorahy, D.J., Gu, X., Andrews, S., Meldrum, C.J., Scott, R.J., Baker, M.S., Macreadie, I.G., Agrez, M.V. Oncogene (2002) [Pubmed]
  22. Heterologous expression and folding analysis of a beta-tubulin isotype from the Antarctic ciliate Euplotes focardii. Pucciarelli, S., Miceli, C., Melki, R. Eur. J. Biochem. (2002) [Pubmed]
  23. Overexpressed Csk tyrosine kinase is localized in focal adhesions, causes reorganization of alpha v beta 5 integrin, and interferes with HeLa cell spreading. Bergman, M., Joukov, V., Virtanen, I., Alitalo, K. Mol. Cell. Biol. (1995) [Pubmed]
  24. Purification and functional characterization of integrin alpha v beta 5. An adhesion receptor for vitronectin. Smith, J.W., Vestal, D.J., Irwin, S.V., Burke, T.A., Cheresh, D.A. J. Biol. Chem. (1990) [Pubmed]
  25. Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit. Ermakova, I., Boldyreff, B., Issinger, O.G., Niefind, K. J. Mol. Biol. (2003) [Pubmed]
  26. Activation and inhibition of G protein-coupled inwardly rectifying potassium (Kir3) channels by G protein beta gamma subunits. Lei, Q., Jones, M.B., Talley, E.M., Schrier, A.D., McIntire, W.E., Garrison, J.C., Bayliss, D.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  27. Differential activity of the G protein beta5 gamma2 subunit at receptors and effectors. Lindorfer, M.A., Myung, C.S., Savino, Y., Yasuda, H., Khazan, R., Garrison, J.C. J. Biol. Chem. (1998) [Pubmed]
  28. Modulation of estrogen receptor-beta isoforms by phytoestrogens in breast cancer cells. Cappelletti, V., Miodini, P., Di Fronzo, G., Daidone, M.G. Int. J. Oncol. (2006) [Pubmed]
  29. A C-helix Residue, Arg-123, Has Important Roles in Both the Active and Inactive Forms of the cAMP Receptor Protein. Youn, H., Kerby, R.L., Koh, J., Roberts, G.P. J. Biol. Chem. (2007) [Pubmed]
  30. P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration. Zhang, H., Li, Z., Viklund, E.K., Strömblad, S. J. Cell Biol. (2002) [Pubmed]
  31. Characterisation of the newly identified human Ump1 homologue POMP and analysis of LMP7(beta 5i) incorporation into 20 S proteasomes. Witt, E., Zantopf, D., Schmidt, M., Kraft, R., Kloetzel, P.M., Krüger, E. J. Mol. Biol. (2000) [Pubmed]
  32. Allorecognition and T cell repertoire selection in severe combined immunodeficiency lacking HLA class II antigens. Knobloch, C., Ballas, M., Wölpl, A., Friedrich, W. Transplantation (1992) [Pubmed]
  33. Enhancement of endothelial cell migration and in vitro tube formation by TAP20, a novel beta 5 integrin-modulating, PKC theta-dependent protein. Tang, S., Gao, Y., Ware, J.A. J. Cell Biol. (1999) [Pubmed]
  34. Integrin alpha v beta 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor alpha 5 beta 1. Blystone, S.D., Graham, I.L., Lindberg, F.P., Brown, E.J. J. Cell Biol. (1994) [Pubmed]
  35. Growth of primary T-cell non-Hodgkin's lymphomata in SCID-hu mice: requirement for a human lymphoid microenvironment. Waller, E.K., Kamel, O.W., Cleary, M.L., Majumdar, A.S., Schick, M.R., Lieberman, M., Weissman, I.L. Blood (1991) [Pubmed]
  36. Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts. Asano, Y., Ihn, H., Yamane, K., Kubo, M., Tamaki, K. Am. J. Pathol. (2004) [Pubmed]
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