Skip to main content
PMC home page
Molecular Pathology : MP logoLink to Molecular Pathology : MP
. 1999 Aug;52(4):208–213. doi: 10.1136/mp.52.4.208

Integrins: a role as cell signalling molecules.

J L Jones 1, R A Walker 1
PMCID: PMC395701  PMID: 10694941

Abstract

Integrins form the major family of proteins that mediates cell-matrix interactions. As well as an adhesive function, it is increasingly apparent that integrins can transduce messages via classic signalling pathways and impact upon such fundamental cellular processes as proliferation, apoptosis, differentiation, and motility. Dysregulation of these processes are a feature of many malignancies. Altered integrin expression has been observed in many human tumours, and perturbation of integrin function or expression in experimental systems has demonstrated that altered integrin signalling may directly contribute to the development of the malignant phenotype.

Full Text

The Full Text of this article is available as a PDF (144.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Assoian R. K. Anchorage-dependent cell cycle progression. J Cell Biol. 1997 Jan 13;136(1):1–4. doi: 10.1083/jcb.136.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Borradori L., Sonnenberg A. Hemidesmosomes: roles in adhesion, signaling and human diseases. Curr Opin Cell Biol. 1996 Oct;8(5):647–656. doi: 10.1016/s0955-0674(96)80106-2. [DOI] [PubMed] [Google Scholar]
  3. Brooks P. C., Strömblad S., Sanders L. C., von Schalscha T. L., Aimes R. T., Stetler-Stevenson W. G., Quigley J. P., Cheresh D. A. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 1996 May 31;85(5):683–693. doi: 10.1016/s0092-8674(00)81235-0. [DOI] [PubMed] [Google Scholar]
  4. Burbelo P. D., Miyamoto S., Utani A., Brill S., Yamada K. M., Hall A., Yamada Y. p190-B, a new member of the Rho GAP family, and Rho are induced to cluster after integrin cross-linking. J Biol Chem. 1995 Dec 29;270(52):30919–30926. doi: 10.1074/jbc.270.52.30919. [DOI] [PubMed] [Google Scholar]
  5. Böhmer R. M., Scharf E., Assoian R. K. Cytoskeletal integrity is required throughout the mitogen stimulation phase of the cell cycle and mediates the anchorage-dependent expression of cyclin D1. Mol Biol Cell. 1996 Jan;7(1):101–111. doi: 10.1091/mbc.7.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen H. C., Guan J. L. Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10148–10152. doi: 10.1073/pnas.91.21.10148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen Q., Kinch M. S., Lin T. H., Burridge K., Juliano R. L. Integrin-mediated cell adhesion activates mitogen-activated protein kinases. J Biol Chem. 1994 Oct 28;269(43):26602–26605. [PubMed] [Google Scholar]
  8. Clarke A. S., Lotz M. M., Chao C., Mercurio A. M. Activation of the p21 pathway of growth arrest and apoptosis by the beta 4 integrin cytoplasmic domain. J Biol Chem. 1995 Sep 29;270(39):22673–22676. doi: 10.1074/jbc.270.39.22673. [DOI] [PubMed] [Google Scholar]
  9. Coppolino M., Leung-Hagesteijn C., Dedhar S., Wilkins J. Inducible interaction of integrin alpha 2 beta 1 with calreticulin. Dependence on the activation state of the integrin. J Biol Chem. 1995 Sep 29;270(39):23132–23138. doi: 10.1074/jbc.270.39.23132. [DOI] [PubMed] [Google Scholar]
  10. Damjanovich L., Albelda S. M., Mette S. A., Buck C. A. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am J Respir Cell Mol Biol. 1992 Feb;6(2):197–206. doi: 10.1165/ajrcmb/6.2.197. [DOI] [PubMed] [Google Scholar]
  11. Datta S. R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M. E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17;91(2):231–241. doi: 10.1016/s0092-8674(00)80405-5. [DOI] [PubMed] [Google Scholar]
  12. Dedhar S., Hannigan G. E. Integrin cytoplasmic interactions and bidirectional transmembrane signalling. Curr Opin Cell Biol. 1996 Oct;8(5):657–669. doi: 10.1016/s0955-0674(96)80107-4. [DOI] [PubMed] [Google Scholar]
  13. Dike L. E., Farmer S. R. Cell adhesion induces expression of growth-associated genes in suspension-arrested fibroblasts. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6792–6796. doi: 10.1073/pnas.85.18.6792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dowling J., Yu Q. C., Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol. 1996 Jul;134(2):559–572. doi: 10.1083/jcb.134.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Elices M. J., Urry L. A., Hemler M. E. Receptor functions for the integrin VLA-3: fibronectin, collagen, and laminin binding are differentially influenced by Arg-Gly-Asp peptide and by divalent cations. J Cell Biol. 1991 Jan;112(1):169–181. doi: 10.1083/jcb.112.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Felding-Habermann B., Mueller B. M., Romerdahl C. A., Cheresh D. A. Involvement of integrin alpha V gene expression in human melanoma tumorigenicity. J Clin Invest. 1992 Jun;89(6):2018–2022. doi: 10.1172/JCI115811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Filardo E. J., Brooks P. C., Deming S. L., Damsky C., Cheresh D. A. Requirement of the NPXY motif in the integrin beta 3 subunit cytoplasmic tail for melanoma cell migration in vitro and in vivo. J Cell Biol. 1995 Jul;130(2):441–450. doi: 10.1083/jcb.130.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Frisch S. M., Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994 Feb;124(4):619–626. doi: 10.1083/jcb.124.4.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Frisch S. M., Vuori K., Ruoslahti E., Chan-Hui P. Y. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996 Aug;134(3):793–799. doi: 10.1083/jcb.134.3.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fukushima Y., Ohnishi T., Arita N., Hayakawa T., Sekiguchi K. Integrin alpha3beta1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells. Int J Cancer. 1998 Mar 30;76(1):63–72. doi: 10.1002/(sici)1097-0215(19980330)76:1<63::aid-ijc11>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  21. Gadbois D. M., Bradbury E. M., Lehnert B. E. Control of radiation-induced G1 arrest by cell-substratum interactions. Cancer Res. 1997 Mar 15;57(6):1151–1156. [PubMed] [Google Scholar]
  22. Giancotti F. G., Ruoslahti E. Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell. 1990 Mar 9;60(5):849–859. doi: 10.1016/0092-8674(90)90098-y. [DOI] [PubMed] [Google Scholar]
  23. Guan J. L., Hynes R. O. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 1990 Jan 12;60(1):53–61. doi: 10.1016/0092-8674(90)90715-q. [DOI] [PubMed] [Google Scholar]
  24. Hall P. A., Coates P., Lemoine N. R., Horton M. A. Characterization of integrin chains in normal and neoplastic human pancreas. J Pathol. 1991 Sep;165(1):33–41. doi: 10.1002/path.1711650107. [DOI] [PubMed] [Google Scholar]
  25. Hannigan G. E., Leung-Hagesteijn C., Fitz-Gibbon L., Coppolino M. G., Radeva G., Filmus J., Bell J. C., Dedhar S. Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase. Nature. 1996 Jan 4;379(6560):91–96. doi: 10.1038/379091a0. [DOI] [PubMed] [Google Scholar]
  26. Huhtala P., Humphries M. J., McCarthy J. B., Tremble P. M., Werb Z., Damsky C. H. Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J Cell Biol. 1995 May;129(3):867–879. doi: 10.1083/jcb.129.3.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hungerford J. E., Compton M. T., Matter M. L., Hoffstrom B. G., Otey C. A. Inhibition of pp125FAK in cultured fibroblasts results in apoptosis. J Cell Biol. 1996 Dec;135(5):1383–1390. doi: 10.1083/jcb.135.5.1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  29. Iwig M., Czeslick E., Müller A., Gruner M., Spindler M., Glaesser D. Growth regulation by cell shape alteration and organization of the cytoskeleton. Eur J Cell Biol. 1995 Jun;67(2):145–157. [PubMed] [Google Scholar]
  30. Jones J. L., Critchley D. R., Walker R. A. Alteration of stromal protein and integrin expression in breast--a marker of premalignant change? J Pathol. 1992 Aug;167(4):399–406. doi: 10.1002/path.1711670409. [DOI] [PubMed] [Google Scholar]
  31. Juliano R. L., Haskill S. Signal transduction from the extracellular matrix. J Cell Biol. 1993 Feb;120(3):577–585. doi: 10.1083/jcb.120.3.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Klein C. E., Dressel D., Steinmayer T., Mauch C., Eckes B., Krieg T., Bankert R. B., Weber L. Integrin alpha 2 beta 1 is upregulated in fibroblasts and highly aggressive melanoma cells in three-dimensional collagen lattices and mediates the reorganization of collagen I fibrils. J Cell Biol. 1991 Dec;115(5):1427–1436. doi: 10.1083/jcb.115.5.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Klein C. E., Steinmayer T., Kaufmann D., Weber L., Bröcker E. B. Identification of a melanoma progression antigen as integrin VLA-2. J Invest Dermatol. 1991 Feb;96(2):281–284. doi: 10.1111/1523-1747.ep12464485. [DOI] [PubMed] [Google Scholar]
  34. Koretz K., Schlag P., Boumsell L., Möller P. Expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in normal mucosa and adenomas of the colon, and in colon carcinomas and their liver metastases. Am J Pathol. 1991 Mar;138(3):741–750. [PMC free article] [PubMed] [Google Scholar]
  35. Nesbit M., Herlyn M. Adhesion receptors in human melanoma progression. Invasion Metastasis. 1994;14(1-6):131–146. [PubMed] [Google Scholar]
  36. Nievers M. G., Schaapveld R. Q., Oomen L. C., Fontao L., Geerts D., Sonnenberg A. Ligand-independent role of the beta 4 integrin subunit in the formation of hemidesmosomes. J Cell Sci. 1998 Jun;111(Pt 12):1659–1672. doi: 10.1242/jcs.111.12.1659. [DOI] [PubMed] [Google Scholar]
  37. Nigro J. M., Aldape K. D., Hess S. M., Tlsty T. D. Cellular adhesion regulates p53 protein levels in primary human keratinocytes. Cancer Res. 1997 Sep 1;57(17):3635–3639. [PubMed] [Google Scholar]
  38. Niu J., Gu X., Turton J., Meldrum C., Howard E. W., Agrez M. Integrin-mediated signalling of gelatinase B secretion in colon cancer cells. Biochem Biophys Res Commun. 1998 Aug 10;249(1):287–291. doi: 10.1006/bbrc.1998.9128. [DOI] [PubMed] [Google Scholar]
  39. Nobes C. D., Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995 Apr 7;81(1):53–62. doi: 10.1016/0092-8674(95)90370-4. [DOI] [PubMed] [Google Scholar]
  40. Novak A., Hsu S. C., Leung-Hagesteijn C., Radeva G., Papkoff J., Montesano R., Roskelley C., Grosschedl R., Dedhar S. Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4374–4379. doi: 10.1073/pnas.95.8.4374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. O'Toole T. E., Katagiri Y., Faull R. J., Peter K., Tamura R., Quaranta V., Loftus J. C., Shattil S. J., Ginsberg M. H. Integrin cytoplasmic domains mediate inside-out signal transduction. J Cell Biol. 1994 Mar;124(6):1047–1059. doi: 10.1083/jcb.124.6.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pignatelli M., Bodmer W. F. Integrin-receptor-mediated differentiation and growth inhibition are enhanced by transforming growth factor-beta in colorectal tumour cells grown in collagen gel. Int J Cancer. 1989 Sep 15;44(3):518–523. doi: 10.1002/ijc.2910440324. [DOI] [PubMed] [Google Scholar]
  43. Pignatelli M., Cardillo M. R., Hanby A., Stamp G. W. Integrins and their accessory adhesion molecules in mammary carcinomas: loss of polarization in poorly differentiated tumors. Hum Pathol. 1992 Oct;23(10):1159–1166. doi: 10.1016/0046-8177(92)90034-z. [DOI] [PubMed] [Google Scholar]
  44. Pignatelli M., Smith M. E., Bodmer W. F. Low expression of collagen receptors in moderate and poorly differentiated colorectal adenocarcinomas. Br J Cancer. 1990 Apr;61(4):636–638. doi: 10.1038/bjc.1990.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schulze A., Zerfass K., Spitkovsky D., Middendorp S., Bergès J., Helin K., Jansen-Dürr P., Henglein B. Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11264–11268. doi: 10.1073/pnas.92.24.11264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schwartz M. A., Schaller M. D., Ginsberg M. H. Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol. 1995;11:549–599. doi: 10.1146/annurev.cb.11.110195.003001. [DOI] [PubMed] [Google Scholar]
  47. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  48. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  49. Streuli C. H., Schmidhauser C., Bailey N., Yurchenco P., Skubitz A. P., Roskelley C., Bissell M. J. Laminin mediates tissue-specific gene expression in mammary epithelia. J Cell Biol. 1995 May;129(3):591–603. doi: 10.1083/jcb.129.3.591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Takada Y., Murphy E., Pil P., Chen C., Ginsberg M. H., Hemler M. E. Molecular cloning and expression of the cDNA for alpha 3 subunit of human alpha 3 beta 1 (VLA-3), an integrin receptor for fibronectin, laminin, and collagen. J Cell Biol. 1991 Oct;115(1):257–266. doi: 10.1083/jcb.115.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tlsty T. D. Cell-adhesion-dependent influences on genomic instability and carcinogenesis. Curr Opin Cell Biol. 1998 Oct;10(5):647–653. doi: 10.1016/s0955-0674(98)80041-0. [DOI] [PubMed] [Google Scholar]
  52. Varner J. A., Emerson D. A., Juliano R. L. Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin. Mol Biol Cell. 1995 Jun;6(6):725–740. doi: 10.1091/mbc.6.6.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Wary K. K., Mainiero F., Isakoff S. J., Marcantonio E. E., Giancotti F. G. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996 Nov 15;87(4):733–743. doi: 10.1016/s0092-8674(00)81392-6. [DOI] [PubMed] [Google Scholar]
  54. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  55. Werb Z., Tremble P. M., Behrendtsen O., Crowley E., Damsky C. H. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol. 1989 Aug;109(2):877–889. doi: 10.1083/jcb.109.2.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Xu L. H., Owens L. V., Sturge G. C., Yang X., Liu E. T., Craven R. J., Cance W. G. Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. Cell Growth Differ. 1996 Apr;7(4):413–418. [PubMed] [Google Scholar]
  57. Yamada K. M., Miyamoto S. Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cell Biol. 1995 Oct;7(5):681–689. doi: 10.1016/0955-0674(95)80110-3. [DOI] [PubMed] [Google Scholar]
  58. Zhu X., Assoian R. K. Integrin-dependent activation of MAP kinase: a link to shape-dependent cell proliferation. Mol Biol Cell. 1995 Mar;6(3):273–282. doi: 10.1091/mbc.6.3.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Zhu X., Ohtsubo M., Böhmer R. M., Roberts J. M., Assoian R. K. Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein. J Cell Biol. 1996 Apr;133(2):391–403. doi: 10.1083/jcb.133.2.391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Zutter M. M., Santoro S. A., Staatz W. D., Tsung Y. L. Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7411–7415. doi: 10.1073/pnas.92.16.7411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. van Duinen C. M., van den Broek L. J., Vermeer B. J., Fleuren G. J., Bruijn J. A. The distribution of cellular adhesion molecules in pigmented skin lesions. Cancer. 1994 Apr 15;73(8):2131–2139. doi: 10.1002/1097-0142(19940415)73:8<2131::aid-cncr2820730818>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]

Articles from Molecular Pathology are provided here courtesy of BMJ Publishing Group

RESOURCES