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Gene Review

TUBB3  -  tubulin, beta 3 class III

Homo sapiens

Synonyms: CDCBM, CDCBM1, CFEOM3, CFEOM3A, FEOM3, ...
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Disease relevance of TUBB3

  • We showed that the beta4 integrin subunit associates with the ErbB-2 tyrosine kinase in human mammary carcinoma cell lines and that its overexpression in NIH3T3/ErbB-2-transformed cells causes a constitutive activation of phosphatidylinositol 3-kinase (PI3K), inducing a strong increase of their invasive capacity [1].
  • Conclusions p53 codon 72 Pro/Pro genotype could be a risk factor for the development of melanoma in the Greek population, especially in subgroups with darker skin pigmentation, as well as among noncarriers of the MC1R red hair polymorphic variants [2].
  • METHODS: Experimental colitis was induced in mice with a frameshift mutation in the MC1R gene (MC1Re/e), C57BL/6 wild type mice, and MC1Re/e-C57BL/6 bone marrow chimeras [3].
  • Apoptosis, which was histologically evident in peritoneal nodules of SCID mice, was induced in the cells with high beta4 subunit expression by attachment to laminin and stimulation with growth factors in vitro [4].
  • An immunohistochemical study of specimens from 120 cases of primary gastric cancer showed that patients with beta4 subunit-positive tumors exhibited peritoneal dissemination only infrequently (P < 0.0001) and had a better outcome (P < 0.01) [4].

Psychiatry related information on TUBB3


High impact information on TUBB3

  • The latter include peptides specific for the alpha 7, alpha 3 beta 2, and alpha 3 beta 4 nicotinic receptor subtypes [10].
  • ErbB2 makes beta 4 integrin an accomplice in tumorigenesis [11].
  • (2006) now demonstrate that alpha 6 beta 4 integrin cooperates with ErbB2 in the formation of mammary tumors and discover distinct pathways that regulate cellular proliferation and adhesion downstream of the ErbB2-integrin complex [11].
  • This absence is likely to result from the lack of alpha 6/beta 4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia [12].
  • A gene (beta 4) encoding a ryanodine receptor (similar to, but distinct from, the muscle RyRs) was identified [13].

Chemical compound and disease context of TUBB3


Biological context of TUBB3

  • Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2]. An additional binding site within the human melanocortin receptor 1 [19]?
  • Moreover, interference with beta4 expression significantly reduces endogenous PI3K activity and AKT and mammalian target of rapamycin phosphorylation [1].
  • On the other hand, the expression of myr-AKT in MCF7 beta4-short hairpin RNA cells rescues the cells from apoptosis in the absence of hormones and upon tamoxifen treatment [1].
  • Deletion of the beta2 subunit also significantly reduced the number of lower-affinity sites insensitive to alpha-bungarotoxin. beta4 Gene deletion partially reduced cytisine-resistant and alpha-bungarotoxin-resistant sites with lower and higher affinity for [3H]epibatidine, respectively [20].
  • In both retinoid sensitive and resistant cells, expression of full-length beta 2 and beta 4 isoforms results in elevated sensitivity to retinoic acid treatment and caspase-independent cell death [21].

Anatomical context of TUBB3

  • All surviving clones, both resistant and sensitive to paclitaxel, displayed reduced expression of the 5beta and beta 4 beta-tubulin isotype transcripts in comparison with the parental cell line [22].
  • Immunoprecipitation studies with subunit-specific antibodies showed that a majority of the nAChRs in the SCG and nodose ganglia contain the alpha3 and beta4 subunits, but a significant percentage of the nAChRs in these ganglia also contain alpha5 and beta2 subunits [23].
  • Site-directed mutagenesis was used to substitute position alpha3 (V7') with four different amino acids (A, F, S, or Y) and coexpressed each mutant subunit with wild-type (WT) beta2 or beta4 subunits in Xenopus oocytes [24].
  • Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) alpha4, alpha5, alpha7, beta2, beta3, and beta4 [25].
  • 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 [26].

Associations of TUBB3 with chemical compounds

  • Neuronal nicotinic acetylcholine receptors are pentamers of homomeric or heteromeric combinations of alpha (alpha2-alpha10) and beta (beta2-beta4) subunits, which have different pharmacological and biophysical properties and locations in the brain [27].
  • CONCLUSIONS: Overall, these results confirm the relevance of beta4 expression in mammary tumors and indicate this integrin as a relevant target for tumor therapy [1].
  • Voltage-Sensitive Oxonol Dyes Are Novel Large-Conductance Ca2+-Activated K+ Channel Activators Selective for beta1 and beta4 but Not for beta2 Subunits [28].
  • To determine the effects of different retinoic acid receptor isoforms on cell proliferation and apoptosis, we transduced retinoid sensitive (MCF7) and retinoid-resistant (MDA-MB-231) cells with retinoic acid receptor beta 2, beta 4, or beta prime [21].
  • CONCLUSION: Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at beta2 but not at beta4- or at alpha7-containing nicotinic receptors [29].

Physical interactions of TUBB3

  • Modeling and experimental validation of the binary complex of the plectin actin-binding domain and the first pair of fibronectin type III (FNIII) domains of the beta4 integrin [30].
  • Glycosylation of the beta4 subunit is not required for its binding to the hSlo channel alpha subunit [31].
  • The corresponding CLCA-binding domain of the beta4 integrin is localized to the specific determining loop (SDL) [32].
  • Its presence in these structures is dependent on the beta 4 cytoplasmic domain but it is not known whether beta 4 interacts directly with keratin filaments or by interaction with other proteins [33].
  • A chimeric beta4 integrin in which the indicated SDL sequence had been replaced with the corresponding sequence from the beta1 integrin failed to bind hCLCA2 [32].

Co-localisations of TUBB3


Regulatory relationships of TUBB3

  • So far, beta3 has only been shown to form functional receptors when expressed together with the alpha3 and beta4 subunits [35].
  • Specifically, we demonstrate that the alpha 6 beta 4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells [36].
  • p38 MAPK is a critical regulator of the constitutive and the beta4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells [37].
  • Taken together, these data show that the pore-forming alpha subunit of the hSlo channel promotes N-linked glycosylation of its auxiliary beta4 subunit, and this in turn influences the modulation of the channel by the beta4 subunit [31].
  • Treatment of mink lung epithelial cells (Mv1Lu) with transforming growth factor beta (TGF-beta) induced expression of the beta 4 gene together with the release of Ca2+ in response to ryanodine (but not in response to caffeine, the other drug active on muscle RyRs) [13].

Other interactions of TUBB3

  • We found also differences in the time-dependent folding of beta2 and beta4 epitopes, which are highly overlapping structures on the loops 1+3 [38].
  • ER-beta4 and -beta5 completely lack helix 12 [39].
  • Unfolding of the cytoplasmic domain may be part of a mechanism by which the interaction of beta4 with other hemidesmosomal components, e.g., BP180, is regulated [40].
  • The tyrosine activation motif located in the connecting segment (CS) of the beta4 cytoplasmic domain was dispensable for HD formation, although it may be involved in the efficient localization of BP180 [40].
  • There is also a functional connection between CD9 and beta4 integrins, as evidenced by anti-CD9 antibody effects on beta4-dependent cell spreading [41].

Analytical, diagnostic and therapeutic context of TUBB3

  • Sequential immunoprecipitation assays indicated that in the SCG, all alpha5 subunits are associated with alpha3 and beta4 subunits, forming the mixed heteromeric alpha3beta4alpha5 subtype [23].
  • RT-PCR analysis revealed expression of alpha3, alpha4, alpha5, alpha7, beta2, and beta4 nAChR subunits [42].
  • On this background we investigated the expression of the nAChR subunits (alpha2-alpha7, alpha9, alpha10, beta2-beta4) on freshly isolated murine alveolar macrophages by immunohistochemistry and RT-PCR [43].
  • Associated with the lack of alpha-MSH response in cultured uveal melanocytes was the absence of expression of the receptor for alpha-MSH (MC1-R), as assessed by Northern blot analysis [44].
  • MC1Re/e mice receiving MC1R+ bone marrow showed a similar course of inflammation to non-transplanted MC1Re/e. Likewise, transplantation of MC1R bone marrow into C57BL/6WT mice did not lead to any worsening of disease [3].


  1. Loss of beta4 integrin subunit reduces the tumorigenicity of MCF7 mammary cells and causes apoptosis upon hormone deprivation. Bon, G., Folgiero, V., Bossi, G., Felicioni, L., Marchetti, A., Sacchi, A., Falcioni, R. Clin. Cancer Res. (2006) [Pubmed]
  2. p53 codon 72 Pro homozygosity increases the risk of cutaneous melanoma in individuals with dark skin complexion and among noncarriers of melanocortin 1 receptor red hair variants. Stefanaki, I., Stratigos, A.J., Dimisianos, G., Nikolaou, V., Papadopoulos, O., Polydorou, D., Gogas, H., Tsoutsos, D., Panagiotou, P., Kanavakis, E., Antoniou, C., Katsambas, A.D. Br. J. Dermatol. (2007) [Pubmed]
  3. Crucial role of the melanocortin receptor MC1R in experimental colitis. Maaser, C., Kannengiesser, K., Specht, C., Lügering, A., Brzoska, T., Luger, T.A., Domschke, W., Kucharzik, T. Gut (2006) [Pubmed]
  4. Integrin alpha6beta4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer. Ishii, Y., Ochiai, A., Yamada, T., Akimoto, S., Yanagihara, K., Kitajima, M., Hirohashi, S. Gastroenterology (2000) [Pubmed]
  5. Sodium channel beta4 subunit: down-regulation and possible involvement in neuritic degeneration in Huntington's disease transgenic mice. Oyama, F., Miyazaki, H., Sakamoto, N., Becquet, C., Machida, Y., Kaneko, K., Uchikawa, C., Suzuki, T., Kurosawa, M., Ikeda, T., Tamaoka, A., Sakurai, T., Nukina, N. J. Neurochem. (2006) [Pubmed]
  6. IL-1 beta decreases expression of amyloid precursor protein gene in human glioma cells. Yang, F., Jansen, L., Friedrichs, W.E., Buchanan, J.M., Bowman, B.H. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  7. Modelling the influence of fat-free mass and physical activity on the decline in maximal oxygen uptake with age in older humans. Amara, C.E., Koval, J.J., Johnson, P.J., Paterson, D.H., Winter, E.M., Cunningham, D.A. Exp. Physiol. (2000) [Pubmed]
  8. Febrile convulsions, ataxia, developmental delay, and obesity: a new syndrome? Lev, D., Watemberg, N., Aviram, A., Fishoff, J., Antman, E., Lerman-Sagie, T. J. Child Neurol. (2001) [Pubmed]
  9. Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. Salas, R., Pieri, F., De Biasi, M. J. Neurosci. (2004) [Pubmed]
  10. Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes. McIntosh, J.M., Santos, A.D., Olivera, B.M. Annu. Rev. Biochem. (1999) [Pubmed]
  11. ErbB2 makes beta 4 integrin an accomplice in tumorigenesis. Muthuswamy, S.K. Cell (2006) [Pubmed]
  12. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Georges-Labouesse, E., Messaddeq, N., Yehia, G., Cadalbert, L., Dierich, A., Le Meur, M. Nat. Genet. (1996) [Pubmed]
  13. Expression of a ryanodine receptor-Ca2+ channel that is regulated by TGF-beta. Giannini, G., Clementi, E., Ceci, R., Marziali, G., Sorrentino, V. Science (1992) [Pubmed]
  14. Expression of alpha-3, alpha-5, and beta-4 neuronal acetylcholine receptor subunit transcripts in normal and myasthenia gravis thymus. Identification of thymocytes expressing the alpha-3 transcripts. Mihovilovic, M., Roses, A.D. J. Immunol. (1993) [Pubmed]
  15. Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly. Dellambra, E., Prislei, S., Salvati, A.L., Madeddu, M.L., Golisano, O., Siviero, E., Bondanza, S., Cicuzza, S., Orecchia, A., Giancotti, F.G., Zambruno, G., De Luca, M. J. Biol. Chem. (2001) [Pubmed]
  16. Conservation of human immunodeficiency virus type 1 gp120 inner-domain sequences in lentivirus and type A and B retrovirus envelope surface glycoproteins. Hötzel, I., Cheevers, W.P. J. Virol. (2001) [Pubmed]
  17. Beta 1 and beta 4 integrin expression in methacarn and formalin-fixed material from in situ ductal carcinoma of the breast. Hanby, A.M., Gillett, C.E., Pignatelli, M., Stamp, G.W. J. Pathol. (1993) [Pubmed]
  18. Destruction of the epithelial anchoring system in lichen planus. Haapalainen, T., Oksala, O., Kallioinen, M., Oikarinen, A., Larjava, H., Salo, T. J. Invest. Dermatol. (1995) [Pubmed]
  19. Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2]. An additional binding site within the human melanocortin receptor 1? Koikov, L.N., Ebetino, F.H., Solinsky, M.G., Cross-Doersen, D., Knittel, J.J. Bioorg. Med. Chem. Lett. (2004) [Pubmed]
  20. Deletion of the alpha7, beta2, or beta4 nicotinic receptor subunit genes identifies highly expressed subtypes with relatively low affinity for [3H]epibatidine. Marks, M.J., Whiteaker, P., Collins, A.C. Mol. Pharmacol. (2006) [Pubmed]
  21. Truncated RAR beta isoform enhances proliferation and retinoid resistance. Swift, M.E., Wallden, B., Wayner, E.A., Swisshelm, K. J. Cell. Physiol. (2006) [Pubmed]
  22. Resistance mechanisms in human sarcoma mutants derived by single-step exposure to paclitaxel (Taxol). Dumontet, C., Duran, G.E., Steger, K.A., Beketic-Oreskovic, L., Sikic, B.I. Cancer Res. (1996) [Pubmed]
  23. Heterogeneity of nicotinic cholinergic receptors in rat superior cervical and nodose Ganglia. Mao, D., Yasuda, R.P., Fan, H., Wolfe, B.B., Kellar, K.J. Mol. Pharmacol. (2006) [Pubmed]
  24. Contribution of valine 7' of TMD2 to gating of neuronal alpha3 receptor subtypes. Nieves-Cintr??n, M., Caballero-Rivera, D., Navedo, M.F., Lasalde-Dominicci, J.A. J. Neurosci. Res. (2006) [Pubmed]
  25. Nicotine: the link between cigarette smoking and the progression of renal injury? Jaimes, E.A., Tian, R.X., Raij, L. Am. J. Physiol. Heart Circ. Physiol. (2007) [Pubmed]
  26. 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]
  27. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Gotti, C., Zoli, M., Clementi, F. Trends Pharmacol. Sci. (2006) [Pubmed]
  28. Voltage-Sensitive Oxonol Dyes Are Novel Large-Conductance Ca2+-Activated K+ Channel Activators Selective for beta1 and beta4 but Not for beta2 Subunits. Morimoto, T., Sakamoto, K., Sade, H., Ohya, S., Muraki, K., Imaizumi, Y. Mol. Pharmacol. (2007) [Pubmed]
  29. Ligands selective for alpha4beta2 but not alpha3beta4 or alpha7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat. Smith, J.W., Mogg, A., Tafi, E., Peacey, E., Pullar, I.A., Szekeres, P., Tricklebank, M. Psychopharmacology (Berl.) (2007) [Pubmed]
  30. Modeling and experimental validation of the binary complex of the plectin actin-binding domain and the first pair of fibronectin type III (FNIII) domains of the beta4 integrin. Litjens, S.H., Wilhelmsen, K., de Pereda, J.M., Perrakis, A., Sonnenberg, A. J. Biol. Chem. (2005) [Pubmed]
  31. Reciprocal modulation between the alpha and beta 4 subunits of hSlo calcium-dependent potassium channels. Jin, P., Weiger, T.M., Levitan, I.B. J. Biol. Chem. (2002) [Pubmed]
  32. The interacting binding domains of the beta(4) integrin and calcium-activated chloride channels (CLCAs) in metastasis. Abdel-Ghany, M., Cheng, H.C., Elble, R.C., Lin, H., DiBiasio, J., Pauli, B.U. J. Biol. Chem. (2003) [Pubmed]
  33. Integrin alpha 6 beta 4 forms a complex with the cytoskeletal protein HD1 and induces its redistribution in transfected COS-7 cells. Niessen, C.M., Hulsman, E.H., Rots, E.S., Sánchez-Aparicio, P., Sonnenberg, A. Mol. Biol. Cell (1997) [Pubmed]
  34. Loss of co-localization of alpha 6 beta 4 integrin and collagen VII in bladder cancer. Liebert, M., Washington, R., Wedemeyer, G., Carey, T.E., Grossman, H.B. Am. J. Pathol. (1994) [Pubmed]
  35. Incorporation of the beta3 Subunit Has a Dominant-Negative Effect on the Function of Recombinant Central-Type Neuronal Nicotinic Receptors. Broadbent, S., Groot-Kormelink, P.J., Krashia, P.A., Harkness, P.C., Millar, N.S., Beato, M., Sivilotti, L.G. Mol. Pharmacol. (2006) [Pubmed]
  36. Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells. Chung, J., Bachelder, R.E., Lipscomb, E.A., Shaw, L.M., Mercurio, A.M. J. Cell Biol. (2002) [Pubmed]
  37. p38 MAPK is a critical regulator of the constitutive and the beta4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells. Mainiero, F., Colombara, M., Antonini, V., Strippoli, R., Merola, M., Poffe, O., Tridente, G., Ramarli, D. Eur. J. Immunol. (2003) [Pubmed]
  38. Time-dependent folding of immunological epitopes of the human chorionic gonadotropin beta-subunit. Roig, J., Krause, J.M., Berger, P., Merz, W.E. Mol. Cell. Endocrinol. (2007) [Pubmed]
  39. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Leung, Y.K., Mak, P., Hassan, S., Ho, S.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  40. Hemidesmosome formation is initiated by the beta4 integrin subunit, requires complex formation of beta4 and HD1/plectin, and involves a direct interaction between beta4 and the bullous pemphigoid antigen 180. Schaapveld, R.Q., Borradori, L., Geerts, D., van Leusden, M.R., Kuikman, I., Nievers, M.G., Niessen, C.M., Steenbergen, R.D., Snijders, P.J., Sonnenberg, A. J. Cell Biol. (1998) [Pubmed]
  41. Palmitoylation supports assembly and function of integrin-tetraspanin complexes. Yang, X., Kovalenko, O.V., Tang, W., Claas, C., Stipp, C.S., Hemler, M.E. J. Cell Biol. (2004) [Pubmed]
  42. Retinoic acid and nerve growth factor induce differential regulation of nicotinic acetylcholine receptor subunit expression in SN56 cells. Nilbratt, M., Friberg, L., Mousavi, M., Marutle, A., Nordberg, A. J. Neurosci. Res. (2007) [Pubmed]
  43. Expression of nicotinic acetylcholine receptors on murine alveolar macrophages. Galvis, G., Lips, K.S., Kummer, W. J. Mol. Neurosci. (2006) [Pubmed]
  44. Uveal Melanocytes Do Not Respond To or Express Receptors for {alpha}-Melanocyte-Stimulating Hormone. Li, L., Hu, D.N., Zhao, H., McCormick, S.A., Nordlund, J.J., Boissy, R.E. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
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