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. 1991 May 2;113(4):907–917. doi: 10.1083/jcb.113.4.907

Integrin alpha 6/beta 4 complex is located in hemidesmosomes, suggesting a major role in epidermal cell-basement membrane adhesion

PMCID: PMC2288991  PMID: 2026654

Abstract

The alpha 6/beta 4 complex is a member of the integrin family of adhesion receptors. It is found on a variety of epithelial cell types, but is most strongly expressed on stratified squamous epithelia. Fluorescent antibody staining of human epidermis suggests that the beta 4 subunit is strongly localized to the basal region showing a similar distribution to that of the 230-kD bullous pemphigoid antigen. The alpha 6 subunit is also strongly localized to the basal region but in addition is present over the entire surfaces of basal cells and some cells in the immediate suprabasal region. By contrast staining for beta 1, alpha 2, and alpha 3 subunits was very weak basally, but strong on all other surfaces of basal epidermal cells. These results suggest that different integrin complexes play differing roles in cell-cell and cell- matrix adhesion in the epidermis. Immunoelectron microscopy showed that the alpha 6/beta 4 complex at the basal epidermal surface is strongly localized to hemidesmosomes. This result provides the first well- characterized monoclonal antibody markers for hemidesmosomes and suggests that the alpha 6/beta 4 complex plays a major role in epidermal cell-basement membrane adhesion. We suggest that the cytoplasmic domains of these transmembrane glycoproteins may contribute to the structure of hemidesmosomal plaques. Immunoultrastructural localization of the BP antigen suggests that it may be involved in bridging between hemidesmosomal plaques and keratin intermediate filaments of the cytoskeleton.

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Selected References

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  1. Aplin J. D., Campbell S., Foden L. J. Adhesion of human amnion epithelial cells to extracellular matrix. Evidence for multiple mechanisms. Exp Cell Res. 1984 Aug;153(2):425–438. doi: 10.1016/0014-4827(84)90611-6. [DOI] [PubMed] [Google Scholar]
  2. Aumailley M., Timpl R., Sonnenberg A. Antibody to integrin alpha 6 subunit specifically inhibits cell-binding to laminin fragment 8. Exp Cell Res. 1990 May;188(1):55–60. doi: 10.1016/0014-4827(90)90277-h. [DOI] [PubMed] [Google Scholar]
  3. Buck C. A., Horwitz A. F. Cell surface receptors for extracellular matrix molecules. Annu Rev Cell Biol. 1987;3:179–205. doi: 10.1146/annurev.cb.03.110187.001143. [DOI] [PubMed] [Google Scholar]
  4. Cartaud A., Ludosky M. A., Courvalin J. C., Cartaud J. A protein antigenically related to nuclear lamin B mediates the association of intermediate filaments with desmosomes. J Cell Biol. 1990 Aug;111(2):581–588. doi: 10.1083/jcb.111.2.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carter W. G., Wayner E. A., Bouchard T. S., Kaur P. The role of integrins alpha 2 beta 1 and alpha 3 beta 1 in cell-cell and cell-substrate adhesion of human epidermal cells. J Cell Biol. 1990 Apr;110(4):1387–1404. doi: 10.1083/jcb.110.4.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Collins J. E., Legan P. K., Kenny T. P., MacGarvie J., Holton J. L., Garrod D. R. Cloning and sequence analysis of desmosomal glycoproteins 2 and 3 (desmocollins): cadherin-like desmosomal adhesion molecules with heterogeneous cytoplasmic domains. J Cell Biol. 1991 Apr;113(2):381–391. doi: 10.1083/jcb.113.2.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dedhar S., Saulnier R. Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol. 1990 Feb;110(2):481–489. doi: 10.1083/jcb.110.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Diaz L. A., Ratrie H., 3rd, Saunders W. S., Futamura S., Squiquera H. L., Anhalt G. J., Giudice G. J. Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J Clin Invest. 1990 Oct;86(4):1088–1094. doi: 10.1172/JCI114812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ellison J., Garrod D. R. Anchoring filaments of the amphibian epidermal-dermal junction traverse the basal lamina entirely from the plasma membrane of hemidesmosomes to the dermis. J Cell Sci. 1984 Dec;72:163–172. doi: 10.1242/jcs.72.1.163. [DOI] [PubMed] [Google Scholar]
  10. Falcioni R., Kennel S. J., Giacomini P., Zupi G., Sacchi A. Expression of tumor antigen correlated with metastatic potential of Lewis lung carcinoma and B16 melanoma clones in mice. Cancer Res. 1986 Nov;46(11):5772–5778. [PubMed] [Google Scholar]
  11. Falcioni R., Sacchi A., Resau J., Kennel S. J. Monoclonal antibody to human carcinoma-associated protein complex: quantitation in normal and tumor tissue. Cancer Res. 1988 Feb 15;48(4):816–821. [PubMed] [Google Scholar]
  12. Giltay J. C., Brinkman H. J., Modderman P. W., von dem Borne A. E., van Mourik J. A. Human vascular endothelial cells express a membrane protein complex immunochemically indistinguishable from the platelet VLA-2 (glycoprotein Ia-IIa) complex. Blood. 1989 Apr;73(5):1235–1241. [PubMed] [Google Scholar]
  13. Green K. J., Parry D. A., Steinert P. M., Virata M. L., Wagner R. M., Angst B. D., Nilles L. A. Structure of the human desmoplakins. Implications for function in the desmosomal plaque. J Biol Chem. 1990 Feb 15;265(5):2603–2612. [PubMed] [Google Scholar]
  14. Green M. A., Sviland L., Malcolm A. J., Pearson A. D. Improved method for immunoperoxidase detection of membrane antigens in frozen sections. J Clin Pathol. 1989 Aug;42(8):875–880. doi: 10.1136/jcp.42.8.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hall D. E., Reichardt L. F., Crowley E., Holley B., Moezzi H., Sonnenberg A., Damsky C. H. The alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers mediate cell attachment to distinct sites on laminin. J Cell Biol. 1990 Jun;110(6):2175–2184. doi: 10.1083/jcb.110.6.2175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hemler M. E., Crouse C., Sonnenberg A. Association of the VLA alpha 6 subunit with a novel protein. A possible alternative to the common VLA beta 1 subunit on certain cell lines. J Biol Chem. 1989 Apr 15;264(11):6529–6535. [PubMed] [Google Scholar]
  17. Hemler M. E., Crouse C., Takada Y., Sonnenberg A. Multiple very late antigen (VLA) heterodimers on platelets. Evidence for distinct VLA-2, VLA-5 (fibronectin receptor), and VLA-6 structures. J Biol Chem. 1988 Jun 5;263(16):7660–7665. [PubMed] [Google Scholar]
  18. Hemler M. E., Huang C., Schwarz L. The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight beta subunit. J Biol Chem. 1987 Mar 5;262(7):3300–3309. [PubMed] [Google Scholar]
  19. Hemler M. E., Huang C., Takada Y., Schwarz L., Strominger J. L., Clabby M. L. Characterization of the cell surface heterodimer VLA-4 and related peptides. J Biol Chem. 1987 Aug 25;262(24):11478–11485. [PubMed] [Google Scholar]
  20. Hemler M. E., Sanchez-Madrid F., Flotte T. J., Krensky A. M., Burakoff S. J., Bhan A. K., Springer T. A., Strominger J. L. Glycoproteins of 210,000 and 130,000 m.w. on activated T cells: cell distribution and antigenic relation to components on resting cells and T cell lines. J Immunol. 1984 Jun;132(6):3011–3018. [PubMed] [Google Scholar]
  21. Hemler M. E. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400. doi: 10.1146/annurev.iy.08.040190.002053. [DOI] [PubMed] [Google Scholar]
  22. Hemler M. E., Ware C. F., Strominger J. L. Characterization of a novel differentiation antigen complex recognize by a monoclonal antibody (A-1A5): unique activation-specific molecular forms on stimulated T cells. J Immunol. 1983 Jul;131(1):334–340. [PubMed] [Google Scholar]
  23. Hogervorst F., Kuikman I., von dem Borne A. E., Sonnenberg A. Cloning and sequence analysis of beta-4 cDNA: an integrin subunit that contains a unique 118 kd cytoplasmic domain. EMBO J. 1990 Mar;9(3):765–770. doi: 10.1002/j.1460-2075.1990.tb08171.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Holton J. L., Kenny T. P., Legan P. K., Collins J. E., Keen J. N., Sharma R., Garrod D. R. Desmosomal glycoproteins 2 and 3 (desmocollins) show N-terminal similarity to calcium-dependent cell-cell adhesion molecules. J Cell Sci. 1990 Oct;97(Pt 2):239–246. doi: 10.1242/jcs.97.2.239. [DOI] [PubMed] [Google Scholar]
  25. Hynes R. O. Integrins: a family of cell surface receptors. Cell. 1987 Feb 27;48(4):549–554. doi: 10.1016/0092-8674(87)90233-9. [DOI] [PubMed] [Google Scholar]
  26. Jones J. C., Yokoo K. M., Goldman R. D. Is the hemidesmosome a half desmosome? An immunological comparison of mammalian desmosomes and hemidesmosomes. Cell Motil Cytoskeleton. 1986;6(6):560–569. doi: 10.1002/cm.970060604. [DOI] [PubMed] [Google Scholar]
  27. Kajiji S., Tamura R. N., Quaranta V. A novel integrin (alpha E beta 4) from human epithelial cells suggests a fourth family of integrin adhesion receptors. EMBO J. 1989 Mar;8(3):673–680. doi: 10.1002/j.1460-2075.1989.tb03425.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kantor R. R., Mattes M. J., Lloyd K. O., Old L. J., Albino A. P. Biochemical analysis of two cell surface glycoprotein complexes, very common antigen 1 and very common antigen 2. Relationship to very late activation T cell antigens. J Biol Chem. 1987 Nov 5;262(31):15158–15165. [PubMed] [Google Scholar]
  29. Kapprell H. P., Owaribe K., Franke W. W. Identification of a basic protein of Mr 75,000 as an accessory desmosomal plaque protein in stratified and complex epithelia. J Cell Biol. 1988 May;106(5):1679–1691. doi: 10.1083/jcb.106.5.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kelly D. E. Fine structure of desmosomes. , hemidesmosomes, and an adepidermal globular layer in developing newt epidermis. J Cell Biol. 1966 Jan;28(1):51–72. doi: 10.1083/jcb.28.1.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kennel S. J., Foote L. J., Falcioni R., Sonnenberg A., Stringer C. D., Crouse C., Hemler M. E. Analysis of the tumor-associated antigen TSP-180. Identity with alpha 6-beta 4 in the integrin superfamily. J Biol Chem. 1989 Sep 15;264(26):15515–15521. [PubMed] [Google Scholar]
  32. Kennel S. J., Foote L. J., Flynn K. M. Tumor antigen on benign adenomas and on murine lung carcinomas quantitated by a two-site monoclonal antibody assay. Cancer Res. 1986 Feb;46(2):707–712. [PubMed] [Google Scholar]
  33. Kimmel K. A., Carey T. E. Altered expression in squamous carcinoma cells of an orientation restricted epithelial antigen detected by monoclonal antibody A9. Cancer Res. 1986 Jul;46(7):3614–3623. [PubMed] [Google Scholar]
  34. Klatte D. H., Kurpakus M. A., Grelling K. A., Jones J. C. Immunochemical characterization of three components of the hemidesmosome and their expression in cultured epithelial cells. J Cell Biol. 1989 Dec;109(6 Pt 2):3377–3390. doi: 10.1083/jcb.109.6.3377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Koch P. J., Walsh M. J., Schmelz M., Goldschmidt M. D., Zimbelmann R., Franke W. W. Identification of desmoglein, a constitutive desmosomal glycoprotein, as a member of the cadherin family of cell adhesion molecules. Eur J Cell Biol. 1990 Oct;53(1):1–12. [PubMed] [Google Scholar]
  36. Larjava H., Peltonen J., Akiyama S. K., Yamada S. S., Gralnick H. R., Uitto J., Yamada K. M. Novel function for beta 1 integrins in keratinocyte cell-cell interactions. J Cell Biol. 1990 Mar;110(3):803–815. doi: 10.1083/jcb.110.3.803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lotz M. M., Korzelius C. A., Mercurio A. M. Human colon carcinoma cells use multiple receptors to adhere to laminin: involvement of alpha 6 beta 4 and alpha 2 beta 1 integrins. Cell Regul. 1990 Feb;1(3):249–257. doi: 10.1091/mbc.1.3.249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Miller K., Mattey D., Measures H., Hopkins C., Garrod D. Localisation of the protein and glycoprotein components of bovine nasal epithelial desmosomes by immunoelectron microscopy. EMBO J. 1987 Apr;6(4):885–889. doi: 10.1002/j.1460-2075.1987.tb04834.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. O'Keefe E. J., Erickson H. P., Bennett V. Desmoplakin I and desmoplakin II. Purification and characterization. J Biol Chem. 1989 May 15;264(14):8310–8318. [PubMed] [Google Scholar]
  40. Parrish E. P., Marston J. E., Mattey D. L., Measures H. R., Venning R., Garrod D. R. Size heterogeneity, phosphorylation and transmembrane organisation of desmosomal glycoproteins 2 and 3 (desmocollins) in MDCK cells. J Cell Sci. 1990 Jun;96(Pt 2):239–248. doi: 10.1242/jcs.96.2.239. [DOI] [PubMed] [Google Scholar]
  41. Peltonen J., Larjava H., Jaakkola S., Gralnick H., Akiyama S. K., Yamada S. S., Yamada K. M., Uitto J. Localization of integrin receptors for fibronectin, collagen, and laminin in human skin. Variable expression in basal and squamous cell carcinomas. J Clin Invest. 1989 Dec;84(6):1916–1923. doi: 10.1172/JCI114379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ruoslahti E., Pierschbacher M. D. New perspectives in cell adhesion: RGD and integrins. Science. 1987 Oct 23;238(4826):491–497. doi: 10.1126/science.2821619. [DOI] [PubMed] [Google Scholar]
  43. Schenk P. The fate of hemidesmosomes in laryngeal carcinoma. Arch Otorhinolaryngol. 1979;222(3):187–198. doi: 10.1007/BF00456315. [DOI] [PubMed] [Google Scholar]
  44. Schwarz M. A., Owaribe K., Kartenbeck J., Franke W. W. Desmosomes and hemidesmosomes: constitutive molecular components. Annu Rev Cell Biol. 1990;6:461–491. doi: 10.1146/annurev.cb.06.110190.002333. [DOI] [PubMed] [Google Scholar]
  45. Shaw L. M., Messier J. M., Mercurio A. M. The activation dependent adhesion of macrophages to laminin involves cytoskeletal anchoring and phosphorylation of the alpha 6 beta 1 integrin. J Cell Biol. 1990 Jun;110(6):2167–2174. doi: 10.1083/jcb.110.6.2167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shienvold F. L., Kelly D. E. The hemidesmosome: new fine structural features revealed by freeze-fracture techniques. Cell Tissue Res. 1976 Sep 20;172(3):289–307. doi: 10.1007/BF00399513. [DOI] [PubMed] [Google Scholar]
  47. Shimizu Y., Van Seventer G. A., Horgan K. J., Shaw S. Regulated expression and binding of three VLA (beta 1) integrin receptors on T cells. Nature. 1990 May 17;345(6272):250–253. doi: 10.1038/345250a0. [DOI] [PubMed] [Google Scholar]
  48. Sonnenberg A., Daams H., Van der Valk M. A., Hilkens J., Hilgers J. Development of mouse mammary gland: identification of stages in differentiation of luminal and myoepithelial cells using monoclonal antibodies and polyvalent antiserum against keratin. J Histochem Cytochem. 1986 Aug;34(8):1037–1046. doi: 10.1177/34.8.2426332. [DOI] [PubMed] [Google Scholar]
  49. Sonnenberg A., Hogervorst F., Osterop A., Veltman F. E. Identification and characterization of a novel antigen complex on mouse mammary tumor cells using a monoclonal antibody against platelet glycoprotein Ic. J Biol Chem. 1988 Oct 5;263(28):14030–14038. [PubMed] [Google Scholar]
  50. Sonnenberg A., Janssen H., Hogervorst F., Calafat J., Hilgers J. A complex of platelet glycoproteins Ic and IIa identified by a rat monoclonal antibody. J Biol Chem. 1987 Jul 25;262(21):10376–10383. [PubMed] [Google Scholar]
  51. Sonnenberg A., Linders C. J., Daams J. H., Kennel S. J. The alpha 6 beta 1 (VLA-6) and alpha 6 beta 4 protein complexes: tissue distribution and biochemical properties. J Cell Sci. 1990 Jun;96(Pt 2):207–217. doi: 10.1242/jcs.96.2.207. [DOI] [PubMed] [Google Scholar]
  52. Sonnenberg A., Linders C. J., Modderman P. W., Damsky C. H., Aumailley M., Timpl R. Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8. J Cell Biol. 1990 Jun;110(6):2145–2155. doi: 10.1083/jcb.110.6.2145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Sonnenberg A., Modderman P. W., Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature. 1988 Dec 1;336(6198):487–489. doi: 10.1038/336487a0. [DOI] [PubMed] [Google Scholar]
  54. Sorokin L., Sonnenberg A., Aumailley M., Timpl R., Ekblom P. Recognition of the laminin E8 cell-binding site by an integrin possessing the alpha 6 subunit is essential for epithelial polarization in developing kidney tubules. J Cell Biol. 1990 Sep;111(3):1265–1273. doi: 10.1083/jcb.111.3.1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Stanley J. R., Hawley-Nelson P., Yuspa S. H., Shevach E. M., Katz S. I. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981 Jun;24(3):897–903. doi: 10.1016/0092-8674(81)90115-x. [DOI] [PubMed] [Google Scholar]
  56. Stanley J. R., Tanaka T., Mueller S., Klaus-Kovtun V., Roop D. Isolation of complementary DNA for bullous pemphigoid antigen by use of patients' autoantibodies. J Clin Invest. 1988 Dec;82(6):1864–1870. doi: 10.1172/JCI113803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Steinberg M. S., Shida H., Giudice G. J., Shida M., Patel N. H., Blaschuk O. W. On the molecular organization, diversity and functions of desmosomal proteins. Ciba Found Symp. 1987;125:3–25. doi: 10.1002/9780470513408.ch2. [DOI] [PubMed] [Google Scholar]
  58. Suzuki S., Naitoh Y. Amino acid sequence of a novel integrin beta 4 subunit and primary expression of the mRNA in epithelial cells. EMBO J. 1990 Mar;9(3):757–763. doi: 10.1002/j.1460-2075.1990.tb08170.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tamura R. N., Rozzo C., Starr L., Chambers J., Reichardt L. F., Cooper H. M., Quaranta V. Epithelial integrin alpha 6 beta 4: complete primary structure of alpha 6 and variant forms of beta 4. J Cell Biol. 1990 Oct;111(4):1593–1604. doi: 10.1083/jcb.111.4.1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Tanaka T., Korman N. J., Shimizu H., Eady R. A., Klaus-Kovtun V., Cehrs K., Stanley J. R. Production of rabbit antibodies against carboxy-terminal epitopes encoded by bullous pemphigoid cDNA. J Invest Dermatol. 1990 May;94(5):617–623. doi: 10.1111/1523-1747.ep12876200. [DOI] [PubMed] [Google Scholar]
  61. Tidman M. J., Eady R. A. Hemidesmosome heterogeneity in junctional epidermolysis bullosa revealed by morphometric analysis. J Invest Dermatol. 1986 Jan;86(1):51–56. doi: 10.1111/1523-1747.ep12283807. [DOI] [PubMed] [Google Scholar]
  62. Trinkaus-Randall V., Gipson I. K. Role of calcium and calmodulin in hemidesmosome formation in vitro. J Cell Biol. 1984 Apr;98(4):1565–1571. doi: 10.1083/jcb.98.4.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Tsukita S., Tsukita S. Desmocalmin: a calmodulin-binding high molecular weight protein isolated from desmosomes. J Cell Biol. 1985 Dec;101(6):2070–2080. doi: 10.1083/jcb.101.6.2070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. WEISS P., FERRIS W. Electronmicrograms of larval amphibian epidermis. Exp Cell Res. 1954 May;6(2):546–549. doi: 10.1016/0014-4827(54)90210-4. [DOI] [PubMed] [Google Scholar]
  65. Westgate G. E., Weaver A. C., Couchman J. R. Bullous pemphigoid antigen localization suggests an intracellular association with hemidesmosomes. J Invest Dermatol. 1985 Mar;84(3):218–224. doi: 10.1111/1523-1747.ep12265229. [DOI] [PubMed] [Google Scholar]
  66. White F. H., Gohari K. Hemidesmosomal dimensions and frequency in experimental oral carcinogenesis: a stereological investigation. Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;45(1):1–13. doi: 10.1007/BF02889847. [DOI] [PubMed] [Google Scholar]

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