Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1996 Dec 2;135(6):1633–1642. doi: 10.1083/jcb.135.6.1633

Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors

PMCID: PMC2133938  PMID: 8978828

Abstract

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Selected References

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

  1. Akiyama S. K., Yamada S. S., Chen W. T., Yamada K. M. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol. 1989 Aug;109(2):863–875. doi: 10.1083/jcb.109.2.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arner E. C., Tortorella M. D. Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin-1. Arthritis Rheum. 1995 Sep;38(9):1304–1314. doi: 10.1002/art.1780380919. [DOI] [PubMed] [Google Scholar]
  3. Blum J. L., Zeigler M. E., Wicha M. S. Regulation of rat mammary gene expression by extracellular matrix components. Exp Cell Res. 1987 Dec;173(2):322–340. doi: 10.1016/0014-4827(87)90274-6. [DOI] [PubMed] [Google Scholar]
  4. Blumer K. J., Johnson G. L. Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci. 1994 Jun;19(6):236–240. doi: 10.1016/0968-0004(94)90147-3. [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. Carraway K. L., Carraway C. A. Signaling, mitogenesis and the cytoskeleton: where the action is. Bioessays. 1995 Feb;17(2):171–175. doi: 10.1002/bies.950170212. [DOI] [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. Chong L. D., Traynor-Kaplan A., Bokoch G. M., Schwartz M. A. The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell. 1994 Nov 4;79(3):507–513. doi: 10.1016/0092-8674(94)90259-3. [DOI] [PubMed] [Google Scholar]
  9. Clark E. A., Brugge J. S. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr 14;268(5208):233–239. doi: 10.1126/science.7716514. [DOI] [PubMed] [Google Scholar]
  10. Damsky C. H., Werb Z. Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol. 1992 Oct;4(5):772–781. doi: 10.1016/0955-0674(92)90100-q. [DOI] [PubMed] [Google Scholar]
  11. Delcommenne M., Streuli C. H. Control of integrin expression by extracellular matrix. J Biol Chem. 1995 Nov 10;270(45):26794–26801. doi: 10.1074/jbc.270.45.26794. [DOI] [PubMed] [Google Scholar]
  12. Fan S. T., Mackman N., Cui M. Z., Edgington T. S. Integrin regulation of an inflammatory effector gene. Direct induction of the tissue factor promoter by engagement of beta 1 or alpha 4 integrin chains. J Immunol. 1995 Apr 1;154(7):3266–3274. [PubMed] [Google Scholar]
  13. Fantl W. J., Johnson D. E., Williams L. T. Signalling by receptor tyrosine kinases. Annu Rev Biochem. 1993;62:453–481. doi: 10.1146/annurev.bi.62.070193.002321. [DOI] [PubMed] [Google Scholar]
  14. Fazioli F., Minichiello L., Matoska V., Castagnino P., Miki T., Wong W. T., Di Fiore P. P. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993 Oct;12(10):3799–3808. doi: 10.1002/j.1460-2075.1993.tb06058.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gadella T. W., Jr, Jovin T. M. Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation. J Cell Biol. 1995 Jun;129(6):1543–1558. doi: 10.1083/jcb.129.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Geiger B., Yehuda-Levenberg S., Bershadsky A. D. Molecular interactions in the submembrane plaque of cell-cell and cell-matrix adhesions. Acta Anat (Basel) 1995;154(1):46–62. doi: 10.1159/000147751. [DOI] [PubMed] [Google Scholar]
  17. Gronowski A. M., Bertics P. J. Evidence for the potentiation of epidermal growth factor receptor tyrosine kinase activity by association with the detergent-insoluble cellular cytoskeleton: analysis of intact and carboxy-terminally truncated receptors. Endocrinology. 1993 Dec;133(6):2838–2846. doi: 10.1210/endo.133.6.8243311. [DOI] [PubMed] [Google Scholar]
  18. Guan J. L., Trevithick J. E., Hynes R. O. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Regul. 1991 Nov;2(11):951–964. doi: 10.1091/mbc.2.11.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gumbiner B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996 Feb 9;84(3):345–357. doi: 10.1016/s0092-8674(00)81279-9. [DOI] [PubMed] [Google Scholar]
  20. Gumbiner B. M. Proteins associated with the cytoplasmic surface of adhesion molecules. Neuron. 1993 Oct;11(4):551–564. doi: 10.1016/0896-6273(93)90068-3. [DOI] [PubMed] [Google Scholar]
  21. Heldin C. H. Dimerization of cell surface receptors in signal transduction. Cell. 1995 Jan 27;80(2):213–223. doi: 10.1016/0092-8674(95)90404-2. [DOI] [PubMed] [Google Scholar]
  22. Hotchin N. A., Hall A. The assembly of integrin adhesion complexes requires both extracellular matrix and intracellular rho/rac GTPases. J Cell Biol. 1995 Dec;131(6 Pt 2):1857–1865. doi: 10.1083/jcb.131.6.1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Jockusch B. M., Bubeck P., Giehl K., Kroemker M., Moschner J., Rothkegel M., Rüdiger M., Schlüter K., Stanke G., Winkler J. The molecular architecture of focal adhesions. Annu Rev Cell Dev Biol. 1995;11:379–416. doi: 10.1146/annurev.cb.11.110195.002115. [DOI] [PubMed] [Google Scholar]
  25. Johnson G. L., Vaillancourt R. R. Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol. 1994 Apr;6(2):230–238. doi: 10.1016/0955-0674(94)90141-4. [DOI] [PubMed] [Google Scholar]
  26. LaFlamme S. E., Akiyama S. K., Yamada K. M. Regulation of fibronectin receptor distribution. J Cell Biol. 1992 Apr;117(2):437–447. doi: 10.1083/jcb.117.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lafrenie R. M., Yamada K. M. Integrin-dependent signal transduction. J Cell Biochem. 1996 Jun 15;61(4):543–553. doi: 10.1002/(sici)1097-4644(19960616)61:4<543::aid-jcb7>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  28. Lemmon M. A., Schlessinger J. Regulation of signal transduction and signal diversity by receptor oligomerization. Trends Biochem Sci. 1994 Nov;19(11):459–463. doi: 10.1016/0968-0004(94)90130-9. [DOI] [PubMed] [Google Scholar]
  29. Lin T. H., Yurochko A., Kornberg L., Morris J., Walker J. J., Haskill S., Juliano R. L. The role of protein tyrosine phosphorylation in integrin-mediated gene induction in monocytes. J Cell Biol. 1994 Sep;126(6):1585–1593. doi: 10.1083/jcb.126.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Matoskova B., Wong W. T., Salcini A. E., Pelicci P. G., Di Fiore P. P. Constitutive phosphorylation of eps8 in tumor cell lines: relevance to malignant transformation. Mol Cell Biol. 1995 Jul;15(7):3805–3812. doi: 10.1128/mcb.15.7.3805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Miyake S., Yagita H., Maruyama T., Hashimoto H., Miyasaka N., Okumura K. Beta 1 integrin-mediated interaction with extracellular matrix proteins regulates cytokine gene expression in synovial fluid cells of rheumatoid arthritis patients. J Exp Med. 1993 Mar 1;177(3):863–868. doi: 10.1084/jem.177.3.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miyamoto S., Akiyama S. K., Yamada K. M. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science. 1995 Feb 10;267(5199):883–885. doi: 10.1126/science.7846531. [DOI] [PubMed] [Google Scholar]
  33. Miyamoto S., Teramoto H., Coso O. A., Gutkind J. S., Burbelo P. D., Akiyama S. K., Yamada K. M. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995 Nov;131(3):791–805. doi: 10.1083/jcb.131.3.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mondal K., Lofquist A. K., Watson J. M., Morris J. S., Price L. K., Haskill J. S. Adhesion and direct integrin engagement differentially regulate gene transcription, transcript stabilization and translation. Biochem Soc Trans. 1995 Aug;23(3):460–464. doi: 10.1042/bst0230460. [DOI] [PubMed] [Google Scholar]
  35. Morino N., Mimura T., Hamasaki K., Tobe K., Ueki K., Kikuchi K., Takehara K., Kadowaki T., Yazaki Y., Nojima Y. Matrix/integrin interaction activates the mitogen-activated protein kinase, p44erk-1 and p42erk-2. J Biol Chem. 1995 Jan 6;270(1):269–273. doi: 10.1074/jbc.270.1.269. [DOI] [PubMed] [Google Scholar]
  36. Parsons J. T. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr Opin Cell Biol. 1996 Apr;8(2):146–152. doi: 10.1016/s0955-0674(96)80059-7. [DOI] [PubMed] [Google Scholar]
  37. Plopper G. E., McNamee H. P., Dike L. E., Bojanowski K., Ingber D. E. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell. 1995 Oct;6(10):1349–1365. doi: 10.1091/mbc.6.10.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Richardson A., Parsons J. T. Signal transduction through integrins: a central role for focal adhesion kinase? Bioessays. 1995 Mar;17(3):229–236. doi: 10.1002/bies.950170309. [DOI] [PubMed] [Google Scholar]
  39. Rosales C., O'Brien V., Kornberg L., Juliano R. Signal transduction by cell adhesion receptors. Biochim Biophys Acta. 1995 Jul 28;1242(1):77–98. doi: 10.1016/0304-419x(95)00005-z. [DOI] [PubMed] [Google Scholar]
  40. Roy L. M., Gittinger C. K., Landreth G. E. Characterization of the epidermal growth factor receptor associated with cytoskeletons of A431 cells. J Cell Physiol. 1989 Aug;140(2):295–304. doi: 10.1002/jcp.1041400215. [DOI] [PubMed] [Google Scholar]
  41. Ruoslahti E. Integrin signaling and matrix assembly. Tumour Biol. 1996;17(2):117–124. doi: 10.1159/000217975. [DOI] [PubMed] [Google Scholar]
  42. Sastry S. K., Horwitz A. F. Integrin cytoplasmic domains: mediators of cytoskeletal linkages and extra- and intracellular initiated transmembrane signaling. Curr Opin Cell Biol. 1993 Oct;5(5):819–831. doi: 10.1016/0955-0674(93)90031-k. [DOI] [PubMed] [Google Scholar]
  43. Sastry S. K., Lakonishok M., Thomas D. A., Muschler J., Horwitz A. F. Integrin alpha subunit ratios, cytoplasmic domains, and growth factor synergy regulate muscle proliferation and differentiation. J Cell Biol. 1996 Apr;133(1):169–184. doi: 10.1083/jcb.133.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schlaepfer D. D., Hanks S. K., Hunter T., van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994 Dec 22;372(6508):786–791. doi: 10.1038/372786a0. [DOI] [PubMed] [Google Scholar]
  45. Schwartz M. A., Denninghoff K. Alpha v integrins mediate the rise in intracellular calcium in endothelial cells on fibronectin even though they play a minor role in adhesion. J Biol Chem. 1994 Apr 15;269(15):11133–11137. [PubMed] [Google Scholar]
  46. Schwartz M. A., Lechene C. Adhesion is required for protein kinase C-dependent activation of the Na+/H+ antiporter by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6138–6141. doi: 10.1073/pnas.89.13.6138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Schwartz M. A. Spreading of human endothelial cells on fibronectin or vitronectin triggers elevation of intracellular free calcium. J Cell Biol. 1993 Feb;120(4):1003–1010. doi: 10.1083/jcb.120.4.1003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sundberg C., Rubin K. Stimulation of beta1 integrins on fibroblasts induces PDGF independent tyrosine phosphorylation of PDGF beta-receptors. J Cell Biol. 1996 Feb;132(4):741–752. doi: 10.1083/jcb.132.4.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996 Apr;8(2):205–215. doi: 10.1016/s0955-0674(96)80067-6. [DOI] [PubMed] [Google Scholar]
  51. Tucker R. W., Meade-Cobun K., Ferris D. Cell shape and increased free cytosolic calcium [Ca2+]i induced by growth factors. Cell Calcium. 1990 Feb-Mar;11(2-3):201–209. doi: 10.1016/0143-4160(90)90071-2. [DOI] [PubMed] [Google Scholar]
  52. Turner C. E., Burridge K. Transmembrane molecular assemblies in cell-extracellular matrix interactions. Curr Opin Cell Biol. 1991 Oct;3(5):849–853. doi: 10.1016/0955-0674(91)90059-8. [DOI] [PubMed] [Google Scholar]
  53. Vaillancourt R. R., Heasley L. E., Zamarripa J., Storey B., Valius M., Kazlauskas A., Johnson G. L. Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation. Mol Cell Biol. 1995 Jul;15(7):3644–3653. doi: 10.1128/mcb.15.7.3644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Vuori K., Ruoslahti E. Tyrosine phosphorylation of p130Cas and cortactin accompanies integrin-mediated cell adhesion to extracellular matrix. J Biol Chem. 1995 Sep 22;270(38):22259–22262. doi: 10.1074/jbc.270.38.22259. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. 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]
  57. 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]
  58. van Bergen en Henegouwen P. M., den Hartigh J. C., Romeyn P., Verkleij A. J., Boonstra J. The epidermal growth factor receptor is associated with actin filaments. Exp Cell Res. 1992 Mar;199(1):90–97. doi: 10.1016/0014-4827(92)90465-k. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES