Review Article
Full Access
Epithelial integrins
Dean Sheppard,
Dean Sheppard
Lung Biology Center of the University of California, San Francisco, USA.
Search for more papers by this authorDean Sheppard,
Dean Sheppard
Lung Biology Center of the University of California, San Francisco, USA.
Search for more papers by this authorAbstract
The integrin family was originally described as a family of adhesion receptors, utilized by cells for attachment to and migration across components of the extracellular matrix. Epithelial cells in adult tissues are generally stationary cells, but these cells nevertheless express several different integrins. This review will discuss the evidence that integrins on epithelial cells are also likely to function as signaling molecules, allowing these cells to detect attachment or detachment, and changes in the local composition of ligands. Signals initiated by integrins appear to modulate epithelial cell differentiation, proliferation, survival, and gene expression. Because the local concentration of integrin ligands is altered by injury, inflammation, and remodeling, signals initiated through integrins are likely to play important roles in the responses of epithelial cells to each of these processes.
References
- 1 Hynes, R. O. (1987). Integrins: a family of cell surface receptors. Cell 48, 549–554.
- 2 Ruoslahti, E., Pierschbacher, M. D. (1987). New perspectives in cell adhesion: RGD and integrins. Science 238, 491–497.
- 3 Cepek, K. L. et al. (1994). Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372, 190–193.
- 4 Juliano, R. L. and Haskill, S. (1993). Signal transduction from the extracellular matrix. J. Cell Biol. 120, 577–585.
- 5 Hynes, R. O. (1992). Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69, 11–25.
- 6 Ruoslahti, E. and Reed, J. C. (1994). Anchorage dependence, integrins, and apoptosis. Cell 77, 477–478.
- 7 Werb, Z., Tremble, P. M., Behrendtsen, O., Crowley, E. and Damsky, C. H. (1989). Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J. Cell Biol. 109, 877–889.
- 8 Streuli, C. H., Bailey, N. and Bissell, M. J. (1991). Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J. Cell Biol. 115, 1383–1395.
- 9 Miyake, S., Yagita, H., Maruyama, T., Hashimoto, H., Miyasaka, N. and Okumura, K. (1993). Beta 1 integrin-mediated interaction with extracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients. J. Exp. Med. 177, 863–868.
- 10 Clark, E. A. and Brugge, J. S. (1995). Integrins and signal transduction pathways: the road taken. Science 268, 233–239.
- 11 Damjanovich, L., Albelda, S. M., Mette, S. A. and Buck, C. (1992). Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am. J. Respir. Cell. Mol. Biol. 6, 197–206.
- 12 Mette, S. A., Pilewski, J., Buck, C. A. and Albelda, S. M. (1993). Distribution of integrin cell adhesion receptors on normal bronchial epithelial cells and lung cancer cells in vitro and in vivo. Am. J. Respir. Cell. Mol. Biol. 8, 562–572.
- 13 Paallysaho, T., Tervo, T., Virtanen, I. and Tervo, K. (1992). Integrins in the normal and healing corneal epithelium. Acta Ophthalmol. Suppl. 202, 22–25.
- 14 Stepp, M. A., Spurr-Michaud, S. and Gipson, I. K. (1993). Integrins in the wounded and unwounded stratified squamous epithelium of the cornea. Invest. Ophthalmol. Vis. Sci. 34, 1829–1844.
- 15 Erle, D. J. and Sheppard, D. (1996). Adhesion receptors and lung disease. In Molecular Eiology of Cell Adhesion Molecules (ed. M. Horton). John Wiley and Sons: Sussex, UK (in press).
- 16 Adams, J. C. and Watt, F. M. (1991). Expression of beta 1, beta 3, beta 4, and beta 5 integrins by human epidermal keratinocytes and non-differentiating keratinocytes. J. Cell Biol. 115, 829–841.
- 17 Watt, F. M. and Jones, P. H. (1993). Expression and function of the keratinocyte integrins. Development Suppl. 185–192.
- 18 Stepp, M. A., Spurr-Michaud, S., Tisdale, A., Elwell, J. and Gipson, I. K. (1990). Alpha 6 beta 4 integrin heterodimer is a component of hemidesmosomes. Proc. Natl Acad. Sci. USA 87, 8970–8974.
- 19 Carter, W. G., Wayner, E. A., Bouchard, T. S. and Kaur, P. (1990). 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. 110, 1387–1404.
- 20 Symington, B. E., Takada, Y. and Carter, W. G. (1993). Interaction of integrins alpha 3 beta 1 and alpha 2 beta 1: potential role in keratinocyte intercellular adhesion. J. Cell Biol. 120, 523–535.
- 21 Sriramarao, P., Steffner, P. and Gehlsen, K. R. (1993). Biochemical evidence for a homophilic interaction of the alpha 3 beta 1 integrin. J. Biol. Chem. 268, 22036–22041.
- 22 Yokosaki, Y., Palmer, E. L., Prieto, A. L., Crossin, K. L., Bourdon, M. A., Pytela, R., Sheppard, D. (1994). The integrin alpha 9 beta 1 mediates cell attachment to a non-RGD site in the third fibronectin type III repeat of tenascin. J. Biol. Chem. 269, 26691–26696.
- 23 Smith, J. W., Vestal, D. J., Irwin, S. V., Burke, T. A. and Cheresh, D. A. (1990). Purification and functional characterization of integrin alpha v beta 5. An adhesion receptor for vitronectin. J. Biol. Chem. 265, 11008–11013.
- 24 Weinacker, A., Ferrando, R., Elliot, M., Hogg, J., Balmes, J. and Sheppard, D. (1995). Distribution of integrins αvβ6 and a9β1 and their known ligands, fibronectin and tenascin, in human airways. Am. J. Respir. Cell. Mol. Biol. 12, 547–557.
- 25 Young, S. L., Chang, L. Y. and Erickson, H. P. (1994). Tenascin-C in rat lung: distribution, ontogeny and role in branching morphogenesis. Dev Biol. 161, 615–625.
- 26 Sheppard, D., Rozzo, C., Starr, L., Quaranta, V., Erle, D. J. and Pytela, R. (1990). Complete amino acid sequence of a novel integrin beta subunit (beta 6) identified in epithelial cells using the polymerase chain reaction. J. Biol. Chem. 265, 11502–11507.
- 27 Sheppard, D., Cohen, D. S., Wang, A. and Busk, M. (1992). Transforming growth factor beta differentially regulates expression of integrin subunits in guinea pig airway epithelial cells. J. Biol. Chem. 267, 17409–17414.
- 28 Breuss, J. M. et al. (1995). Expression of the β6 integrin in development, neoplasia, and tissue repair suggests a role in epithelial remodeling. J. Cell Sci. 108, 2241–2251.
- 29 Prieto, A. L., Edelman, G. M. and Crossin, K. L. (1993). Multiple integrins mediate cell attachment to cytotactin/tenascin. Proc. Natl Acad. Sci. 90, 10154–10158.
- 30 Burridge, K. and Fath, K. (1989). Focal contacts: transmembrane links between the extracellular matrix and the cytoskeleton. BioEssays 10, 104–108.
- 31 Otey, C. A., Pavalko, F. M. and Burridge, K. (1990). An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J. Cell Biol. 111, 721–729.
- 32 Johnson, R. P. and Craig, S. W. (1995). F-actin binding site masked by the inramolecular association of vinculin head and tail domains. Nature 273, 261–264.
- 33 Guadagno, T. M., Ohtsubo, M., Roberts, J. M. and Assoian, R. K. (1993). A link between cyclin A expression and adhesion-dependent cell cycle progression. Science ?? 1572–1575.
- 34 Hansen, L., Mooney, D., Vacanti, J. P. and Ingber, D. E. (1994). Integrin binding and cell spreading on extracellular matrix act at different points in the cell cycle to promote hepatocyte growth. Mol. Biol. Cell. 5, 967–975.
- 35 Bartfeld, N. S., Pasquale, E. B., Geltosky, J. E. and Languino, L. R. (1993). The alpha v beta 3 integrin associates with a 190-kDa protein that is phosphorylated on tyrosine in response to platelet-derived growth factor. J. Biol. Chem. 268, 17270–17276.
- 36 Bellas, R. E., Bendori, R. and Farmer, S. R. (1991). Epidermal growth factor activation of vinculin and beta 1-integrin gene transcription in quiescent Swiss 3T3 cells. Regulation through a protein kinase C-independent pathway. J. Biol. Chem. 266, 12008–12014.
- 37 Chen, J. D., Kim, J. P., Zhang, K., Sarret, Y., Wynn, K. C., Kramer, R. H. and Woodley, D. T. (1993). Epidermal growth factor (EGF) promotes human keratinocyte locomotion on collagen by increasing the alpha 2 integrin subunit. Exp. Cell Res. 209, 216–223.
- 38 Schlaepfer, D. D., Hanks, S. K., Hunter, T. and van der Geer, P. (1994). Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 372, 786–791.
- 39 Chen, Q., Kinch, M. S., Lin, T. H., Burridge, K. and Juliano, R. L. (1994). Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J. Biol Chem. 269, 26602–26605.
- 40 Kornberg, L., Earp, H. S., Parsons, J. T., Schaller, M. and Juliano, R. L. (1992). Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J. Biol Chem. 267, 23439–23442.
- 41 Knight, J. B., Yamauchi, K. and Pessin, J. E. (1995). Divergent insulin and platelet-derived growth factor regulation of focal adhesion kinase (pp 125FAK) tyrosine phosphorylation and rearrangement of actin stress fibers. J. Biol Chem. 270, 10199–10203.
- 42 Varner, J. A., Emerson, D. A. and Juliano, R. L. (1995). Integrin α5β1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol. Biol. Cell. 6, 725–740.
- 43 Symington, B. E. (1990). Fibronectin receptor overexpression and loss of transformed phenotype in a stable variant of the K562 cell line. Cell Regul. 1, 637–648.
- 44 Giancotti, F. G. and Ruoslhti, E. (1990). Elevated levels of the α5β1 receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell 60, 849–859.
- 45 Jones, P. H. and Watt, F. M. (1993). Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73, 713–724.
- 46 Jones, P. H., Harper, S. and Watt, F. M. (1995). Stem cell patterning and fate in human epidermis. Cell 80, 83–93.
- 47 Carroll, J. M., Romero, M. R. and Watt, F. M. (1995). Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resmbling psoriasis. Cell 83, 957–968.
- 48 Tournier, J.-M., Goldstein, G. A., Hall, D. E., Damsky, C. H. and Basbaum, C. B. (1992). Extracellular matrix proteins regulate morphologic and biochemical properties of tracheal gland serous cells through integrins. Am. J. Respir. Cell. Mol. Biol. 6, 461–471.
- 49 Schoenenberger, C. A., Zuk, A., Zinkl, G. M., Kendall, D. and Matlin, K. S. (1994). Integrin expression and localization in normal MDCK cells and transformed MDCK cells lacking apical polarity. J. Cell Sci. 107, 527–541.
- 50 Rizzolo, L. J. (1991). Basement membrane stimulates the polarized distribution of integrins but not the Na,K-ATPase in the retinal pigment epithelium. Cell Regul. 2, 939–949.
- 51 Ojakian, G. K. and Schwimmer, R. (1994). Regulation of epithelial cell surface polarity reversal by beta 1 integrins. J. Cell Sci. 107, 561–576.
- 52 Keely, P. J., Fong, A. M., Zutter, M. M. and Santoro, S. A. (1995). Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells. J. Cell Sci. 108, 595–607.
- 53 Agrez, M., Chen, A., Cone, R. I., Pytela, R. and Sheppard, D. (1994). The αvβ6 integrin promotes proliferation of colon carcinoma cells through a unique region of the β6 cytoplasmic domain. J. Cell Biol. 127, 547–556.
- 54 Boudreau, N., Sympson, C. J., Werb, Z. and Bissell, M. J. (1995). Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267, 891–894.
- 55 Bates, R. C., Buret, A., van Helden, D. F., Horton, M. A. and Burns, G. F. (1994). Apoptosis induced by inhibition of intercellular contact. J. Cell Biol. 125, 403–415.
- 56 Becker, S., Quay, J., Koren, H. S. and Haskill, J. S. (1994). Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J. Physiol. 266, L278–286.
- 57
Bedard, M.,
McClure, C. D.,
Schiller, N. L.,
Francoeur, C.,
Cantin, A. and
Denis, M.
(1993).
Release of interleukin-8, interleukin-6, and colony-stimulating factors by upper airway epithelial cells: implications for cystic fibrosis.
Am. J. Respir. Cell. Mol. Biol.
9, 455–462.
10.1165/ajrcmb/9.4.455 Google Scholar
- 58 Churchill, L. Friedman, B., Schleimer, R. P. and Proud, D. (1992). Production of granulocyte-macrophage colony-stimulating factor by cultured human tracheal epithelial cells. Immunology 75, 189–195.
- 59 Rot, A., Krieger, M., Brunner, T., Bischoff, S. C., Schall, T. J. and Dahinden, C. A. (1992). RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J. Exp Med. 176, 1489–1495.
- 60 Lukacs, N. W., Strieter, R. M., Shaklee, C. L. and Chensue, S. W. (1995). Macrophage inflammatory protein-1 alpha influences eosinophil recruitment in antigen-specific airway inflammation. Eur. J. Immunol. 25, 245–251.
- 61 Elias, J. A., Zheng, T., Einarsson, O., Landry, M., Trow, T., Rebert, N. and Panuska, J. (1994). Epithelial interleukin-11. Regulation by cytokines, respiratory syncytial virus, and retinoic acid. J. Biol. Chem. 269, 22261–22268.
- 62 Marini, M., Vittori, E., Hollemborg, J. and Mattoli, S. (1992). Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J., Allergy Clin. Immunol. 89, 1001–1009.
- 63 Huang, X.-Z., Wu, J. F., Cass, D., Erle, D. J., Corry, D., Young, S. G., Farese, R. V. and Jr, Sheppard, D. (1996). Inactivation of the β6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lungs and skin. J. Cell Biol. (in press).
- 64 Gailit, J., Welch, M. P. and Clark, R. A. (1994). TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. J. Invest Dermatol. 103, 221–227.
- 65 Matthay, M. A., Thiery, J. P., Lafont, F., Stampfer, F. and Boyer, B. (1993). Transient effect of epidermal growth factor on the motility of an immortalized mammary epithelial cell line. J. Cell Sci. 106, 869–878.
