Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Ras GTPases: integrins' friends or foes?

Nature Reviews Molecular Cell Biology volume 4, pages 767–777 (2003)Cite this article

A Correction to this article was published on 01 January 2004

Key Points

  • As the main surface receptors that connect cells to the extracellular matrix (ECM), integrins control cell adhesion and migration — the fundamental cell behaviours that underlie development, immune responses and tumorigenesis in animals. As the essential link between ECM and cytoskeleton, integrins relay signals from the ECM to prompt intracellular signal cascades as well as to reshape cell topology in a process termed 'outside–in' signalling. But intracellular interactions can determine the affinity of integrins for their ligands through 'inside–out' signalling.

  • Ras proteins are small GTPases that alternate between GTP-bound and GDP-bound forms, which correspond to their active and inactive conformations, respectively. Ras proteins impart profound effects on the affinity and avidity of integrins. Ras, R-ras and Rap1 are the best studied in this respect.

  • H-ras can either suppress or activate integrin, depending on cellular context and the type of integrin it affects. Raf1 and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) might mediate the suppression of integrins by Ras under certain circumstances, whereas phosphatidylinositol 3-kinase (PI3K) could enable Ras to activate integrins.

  • R-ras is an activator of integrins that can convert suspension cells into highly adherent ones. R-ras employs PI3K to effect its activation of integrins in haematopoietic cells, but not in fibroblasts.

  • Like R-ras, Rap1 is an integrin activator. Rap1 can maintain integrins in their active conformation and can promote integrin clustering to enhance avidity. RapL, a newly identified Rap1 effector, might connect Rap1 and integrin in lymphocytes.

  • There is substantial crosstalk among Ras proteins in their regulation of integrin. R-ras counters the suppressive effect of Ras on integrins in fibroblasts. R-ras might also activate integrins through Rap1.

Abstract

Integrins are cell-surface receptors that mediate and coordinate cellular responses to the extracellular matrix (ECM). Cellular signalling pathways can regulate cell adhesion by altering the affinity and avidity of integrins for ECM. The Ras family of small G proteins, which includes H-ras, R-ras and Rap, are important elements in cellular signalling pathways that control integrin function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic of integrin interaction with ECM and intracellular proteins.
Figure 2: H-ras-mediated integrin regulation in fibroblasts.
Figure 3: Rap-mediated integrin activation.

Similar content being viewed by others

References

  1. The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018 (1998).

  2. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195 (2000).

    PubMed  Google Scholar 

  3. Cheresh, D. A. & Mecham, R. P. Integrins: molecular and biological responses to the extracellular matrix. (Academic Press, London, 1994).

    Google Scholar 

  4. Haas, T. A. & Plow, E. F. Integrin-ligand interactions: a year in review. Curr. Opin. Cell. Biol. 6, 656–662 (1994).

    CAS  PubMed  Google Scholar 

  5. Loftus, J. C., Smith, J. W. & Ginsberg, M. H. Integrin-mediated cell adhesion: the extracellular face. J. Biol. Chem. 269, 25235–25238 (1994).

    CAS  PubMed  Google Scholar 

  6. Ginsberg, M. H., Loftus, J. C. & Plow, E. F. Common and ligand-specific integrin recognition mechanisms. Chem. Immunol. 50, 75–88 (1991).

    CAS  PubMed  Google Scholar 

  7. Liu, S., Calderwood, D. A. & Ginsberg, M. H. Integrin cytoplasmic domain-binding proteins. J. Cell Sci. 113, 3563–3571 (2000).

    CAS  PubMed  Google Scholar 

  8. Liddington, R. C. & Ginsberg, M. H. Integrin activation takes shape. J. Cell Biol. 158, 833–839 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hughes, P. E. et al. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J. Biol. Chem. 271, 6571–6574 (1996).

    CAS  PubMed  Google Scholar 

  10. Takagi, J., Erickson, H. P. & Springer, T. A. C-terminal opening mimics 'inside-out' activation of integrin α5β1 . Nature Struct. Biol. 8, 412–416 (2001).

    CAS  PubMed  Google Scholar 

  11. Shimaoka, M., Takagi, J. & Springer, T. A. Conformational regulation of integrin structure and function. Annu. Rev. Biophys. Biomol. Struct. 31, 485–516 (2002).

    CAS  PubMed  Google Scholar 

  12. Reuther, G. W. & Der, C. J. The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr. Opin. Cell Biol. 12, 157–165 (2000).

    CAS  PubMed  Google Scholar 

  13. Lee, C. H., Della, N. G., Chew, C. E. & Zack, D. J. Rin, a neuron-specific and calmodulin-binding small G-protein, and Rit define a novel subfamily of ras proteins. J. Neurosci. 16, 6784–6794 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Shao, H., Kadono-Okuda, K., Finlin, B. S. & Andres, D. A. Biochemical characterization of the Ras-related GTPases Rit and Rin. Arch. Biochem. Biophys. 371, 207–219 (1999).

    CAS  PubMed  Google Scholar 

  15. Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der, C. J. Understanding Ras: 'it ain't over 'til it's over'. Trends Cell. Biol. 10, 147–154 (2000).

    CAS  PubMed  Google Scholar 

  16. Kitayama, H., Sugimoto, Y., Matsuzaki, T., Ikawa, Y. & Noda, M. A ras-related gene with transformation suppressor activity. Cell 56, 77–84 (1989).

    CAS  PubMed  Google Scholar 

  17. Hughes, P. E. et al. Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell 88, 521–530 (1997).

    CAS  PubMed  Google Scholar 

  18. Hughes, P. E. et al. Suppression of integrin activation by activated Ras or Raf does not correlate with bulk activation of ERK MAP kinase. Mol. Biol. Cell 13, 2256–2265 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kashiwagi, H. et al. Affinity modulation of platelet integrin αIIbβ3 by β3-endonexin, a selective binding partner of the β3 integrin cytoplasmic tail. J. Cell Biol. 137, 1433–1443 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sechler, J. L., Cumiskey, A. M., Gazzola, D. M. & Schwarzbauer, J. E. A novel RGD-independent fibronectin assembly pathway initiated by α4β1 integrin binding to the alternatively spliced V region. J. Cell Sci. 113, 1491–1498 (2000).

    CAS  PubMed  Google Scholar 

  21. Liu, Z. J. et al. A novel role for H-Ras in the regulation of very late antigen-4 integrin and VCAM-1 via c-Myc-dependent and -independent mechanisms. J. Immunol. 163, 4901–4908 (1999).

    CAS  PubMed  Google Scholar 

  22. Shibayama, H. et al. H-Ras is involved in the inside-out signaling pathway of interleukin-3-induced integrin activation. Blood 93, 1540–1548 (1999).

    CAS  PubMed  Google Scholar 

  23. Fujimoto, H. et al. Down-regulation of α6 integrin, an anti-oncogene product, by functional cooperation of H-Ras and c-Myc. Genes Cells 6, 337–343 (2001).

    CAS  PubMed  Google Scholar 

  24. Myou, S. et al. Blockade of focal clustering and active conformation in β2-integrin-mediated adhesion of eosinophils to intercellular adhesion molecule-1 caused by transduction of HIV TAT-dominant negative Ras. J. Immunol. 169, 2670–2676 (2002).

    CAS  PubMed  Google Scholar 

  25. Tanaka, Y. et al. H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells. J. Immunol. 163, 6209–6216 (1999).

    CAS  PubMed  Google Scholar 

  26. Sethi, T., Ginsberg, M. H., Downward, J. & Hughes, P. E. The small GTP-binding protein R-Ras can influence integrin activation by antagonizing a Ras/Raf-initiated integrin suppression pathway. Mol. Biol. Cell 10, 1799–1809 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kinashi, T. et al. Distinct mechanisms of α5β1 integrin activation by Ha-Ras and R-Ras. J. Biol. Chem. 275, 22590–22596 (2000).

    CAS  PubMed  Google Scholar 

  28. Ramos, J. W., Kojima, T. K., Hughes, P. E., Fenczik, C. A. & Ginsberg, M. H. The death effector domain of PEA-15 is involved in its regulation of integrin activation. J. Biol. Chem. 273, 33897–33900 (1998).

    CAS  PubMed  Google Scholar 

  29. Matter, M. L., Ginsberg, M. H. & Ramos, J. W. Identification of cell signaling molecules by expression cloning. Sci. STKE 103, PL9 (2001).

    Google Scholar 

  30. Kitsberg, D. et al. Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFα-induced apoptosis. J. Neurosci. 19, 8244–8251 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Formstecher, E. et al. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell. 1, 239–250 (2001).

    CAS  PubMed  Google Scholar 

  32. Zhang, Z., Vuori, K., Wang, H., Reed, J. C. & Ruoslahti, E. Integrin activation by R-ras. Cell 85, 61–69 (1996). Demonstrated for the first time the involvement of R-ras in intergin regulation by converting suspension cells into adherent cells with R-ras.

    CAS  PubMed  Google Scholar 

  33. Keely, P. J., Rusyn, E. V., Cox, A. D. & Parise, L. V. R-Ras signals through specific integrin α cytoplasmic domains to promote migration and invasion of breast epithelial cells. J. Cell. Biol. 145, 1077–1088 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Self, A. J., Caron, E., Paterson, H. F. & Hall, A. Analysis of R-Ras signalling pathways. J. Cell. Sci. 114, 1357–1366 (2001).

    CAS  PubMed  Google Scholar 

  35. Ivins, J. K., Yurchenco, P. D. & Lander, A. D. Regulation of neurite outgrowth by integrin activation. J. Neurosci. 20, 6551–6560 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Caron, E., Self, A. J. & Hall, A. The GTPase Rap1 controls functional activation of macrophage integrin αMβ2 by LPS and other inflammatory mediators. Curr. Biol. 10, 974–978 (2000).

    CAS  PubMed  Google Scholar 

  37. Wang, B., Zou, J. X., Ek-Rylander, B. & Ruoslahti, E. R-Ras contains a proline-rich site that binds to SH3 domains and is required for integrin activation by R-Ras. J. Biol. Chem. 275, 5222–5227 (2000).

    CAS  PubMed  Google Scholar 

  38. Hansen, M. et al. R-Ras C-terminal sequences are sufficient to confer R-Ras specificity to H-Ras. Oncogene 21, 4448–4461 (2002).

    CAS  PubMed  Google Scholar 

  39. Oertli, B. et al. The effector loop and prenylation site of R-Ras are involved in the regulation of integrin function. Oncogene 19, 4961–4969 (2000).

    CAS  PubMed  Google Scholar 

  40. Berrier, A. L., Mastrangelo, A. M., Downward, J., Ginsberg, M. & LaFlamme, S. E. Activated R-ras, Rac1, PI 3-kinase and PKCε can each restore cell spreading inhibited by isolated integrin β1 cytoplasmic domains. J. Cell Biol. 151, 1549–1560 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Nimnual, A. S., Yatsula, B. A. & Bar-Sagi, D. Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. Science 279, 560–563 (1998).

    CAS  PubMed  Google Scholar 

  42. Han, J. et al. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279, 558–560 (1998).

    CAS  PubMed  Google Scholar 

  43. Michiels, F. et al. Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and c-Jun NH2-terminal kinase activation. J. Cell Biol. 137, 387–398 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Storz, P. & Toker, A. 3′-phosphoinositide-dependent kinase-1 (PDK-1) in PI3-kinase signaling. Front. Biosci. 7, d886–d902 (2002).

    CAS  PubMed  Google Scholar 

  45. Cenni, V. et al. Regulation of novel protein kinase Cε by phosphorylation. Biochem. J. 363, 537–545 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsukamoto, N., Hattori, M., Yang, H., Bos, J. L. & Minato, N. Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. J. Biol. Chem. 274, 18463–18469 (1999).

    CAS  PubMed  Google Scholar 

  47. Katagiri, K. et al. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol. Cell. Biol. 20, 1956–1969 (2000). Provided the direct evidence for Rap1 involvement in integrin-mediated cell adhesion.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shimonaka, M. et al. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell. Biol. 161, 417–427 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Katagiri, K., Hattori, M., Minato, N. & Kinashi, T. Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses. Mol. Cell. Biol. 22, 1001–1015 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Enserink, J. M. et al. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nature Cell. Biol. 4, 901–906 (2002).

    CAS  PubMed  Google Scholar 

  51. Arai, A. et al. Rap1 is activated by erythropoietin or interleukin-3 and is involved in regulation of β1 integrin-mediated hematopoietic cell adhesion. J. Biol. Chem. 276, 10453–10462 (2001).

    CAS  PubMed  Google Scholar 

  52. Bos, J. L., de Rooij, J. & Reedquist, K. A. Rap1 signalling: adhering to new models. Nature Rev. Mol. Cell. Biol. 2, 369–377 (2001).

    CAS  Google Scholar 

  53. Fenczik, C. A. et al. Distinct domains of CD98hc regulate integrins and amino acid transport. J. Biol. Chem. 276, 8746–8752 (2001).

    CAS  PubMed  Google Scholar 

  54. Fenczik, C. A., Sethi, T., Ramos, J. W., Hughes, P. E. & Ginsberg, M. H. Complementation of dominant suppression implicates CD98 in integrin activation. Nature 390, 81–85 (1997).

    CAS  PubMed  Google Scholar 

  55. Suga, K. et al. CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of Rap1. FEBS Lett. 489, 249–253 (2001).

    CAS  PubMed  Google Scholar 

  56. Reedquist, K. A. et al. The small GTPase, Rap1, mediates CD31-induced integrin adhesion. J. Cell Biol. 148, 1151–1158 (2000). Provided direct evidence that Rap1 is involved in integrin-mediated adhesion downstream of CD31.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sebzda, E., Bracke, M., Tugal, T., Hogg, N. & Cantrell, D. A. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nature Immunol. 3, 251–258 (2002). Provided in vivo evidence that Rap1 stimulates the immune response as opposed to causing anergy and suggested that Rap1 acts through stimulating LFA-1-mediated adhesion.

    CAS  Google Scholar 

  58. Amsen, D., Kruisbeek, A., Bos, J. L. & Reedquist, K. Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection. Eur. J. Immunol. 30, 2832–2841 (2000).

    CAS  PubMed  Google Scholar 

  59. Stone, J. D. et al. Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-ζ, and ZAP-70. J. Immunol. 158, 5773–5782 (1997).

    CAS  PubMed  Google Scholar 

  60. Tang, Q. et al. The Src family kinase Fyn mediates signals induced by TCR antagonists. J. Immunol. 168, 4480–4487 (2002).

    CAS  PubMed  Google Scholar 

  61. Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nature Immunol. 3, 1192–1199 (2002).

    CAS  Google Scholar 

  62. Ohba, Y. et al. Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J. 20, 3333–3341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Rangarajan, S. et al. Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the β2-adrenergic receptor. J. Cell Biol. 160, 487–493 (2003). Demonstrated for the first time the requirement of endogenous Rap for integrin activation by the use of 8-pCPT-2′- O -Me-cAMP, a specific activator of the RapGEF Epac.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bertoni, A. et al. Relationships between Rap1b, affinity modulation of integrin αIIbβ3, and the actin cytoskeleton. J. Biol. Chem. 277, 25715–25721 (2002). Demonstrated the requirement for Rap1 in maintaining integrin in an active conformation.

    CAS  PubMed  Google Scholar 

  65. de Bruyn, K. M., Rangarajan, S., Reedquist, K. A., Figdor, C. G. & Bos, J. L. The small GTPase Rap1 is required for Mn(2+)- and antibody-induced LFA-1- and VLA-4-mediated cell adhesion. J. Biol. Chem. 277, 29468–29476 (2002).

    CAS  PubMed  Google Scholar 

  66. Katagiri, K., Maeda, A., Shimonaka, M. & Kinashi, T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nature Immunol. 4, 741–748 (2003). Identified Nore1/RapL as the Rap effector that might provide Rap with a direct link to integrin activation.

    CAS  Google Scholar 

  67. Tommasi, S. et al. RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene 21, 2713–2720 (2002).

    CAS  PubMed  Google Scholar 

  68. Ohba, Y., Kurokawa, K. & Matsuda, M. Mechanism of the spatio–temporal regulation of Ras and Rap1. EMBO J. 22, 859–869 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Marte, B. M., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr. Biol. 7, 63–70 (1997).

    CAS  PubMed  Google Scholar 

  70. Gao, X. et al. Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras. J. Biol. Chem. 276, 42219–42225 (2001).

    CAS  PubMed  Google Scholar 

  71. O'Toole, T. E. et al. Integrin cytoplasmic domains mediate inside-out signal transduction. J. Cell Biol. 124, 1047–1059 (1994).

    CAS  PubMed  Google Scholar 

  72. Calderwood, D. A. et al. The phosphotyrosine binding-like domain of talin activates integrins. J. Biol. Chem. 277, 21749–21758 (2002).

    CAS  PubMed  Google Scholar 

  73. Brown, N. H. et al. Talin is essential for integrin function in Drosophila. Dev. Cell 3, 569–579 (2002).

    CAS  PubMed  Google Scholar 

  74. Yan, B., Calderwood, D. A., Yaspan, B. & Ginsberg, M. H. Calpain cleavage promotes talin binding to the β3 integrin cytoplasmic domain. J. Biol. Chem. 276, 28164–28170 (2001).

    CAS  PubMed  Google Scholar 

  75. Martel, V. et al. Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. J. Biol. Chem. 276, 21217–21227 (2001).

    CAS  PubMed  Google Scholar 

  76. Manes, S. et al. Membrane raft microdomains in chemokine receptor function. Semin. Immunol. 13, 147–157 (2001).

    CAS  PubMed  Google Scholar 

  77. Pande, G. The role of membrane lipids in regulation of integrin functions. Curr. Opin. Cell. Biol. 12, 569–574 (2000).

    CAS  PubMed  Google Scholar 

  78. Zhao, J., Kung, H. F. & Manne, V. Farnesylation of p21 Ras proteins in Xenopus oocytes. Cell. Mol. Biol. Res. 40, 313–321 (1994).

    CAS  PubMed  Google Scholar 

  79. Rowell, C. A., Kowalczyk, J. J., Lewis, M. D. & Garcia, A. M. Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J. Biol. Chem. 272, 14093–14097 (1997).

    CAS  PubMed  Google Scholar 

  80. Dong, D. L., Liu, R., Sherlock, R., Wigler, M. H. & Nestler, H. P. Molecular forceps from combinatorial libraries prevent the farnesylation of Ras by binding to its carboxyl terminus. Chem. Biol. 6, 133–141 (1999).

    CAS  PubMed  Google Scholar 

  81. Boyartchuk, V. L., Ashby, M. N. & Rine, J. Modulation of Ras and a-factor function by carboxyl-terminal proteolysis. Science 275, 1796–1800 (1997).

    CAS  PubMed  Google Scholar 

  82. Hancock, J. F., Cadwallader, K. & Marshall, C. J. Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). EMBO J. 10, 641–646 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Volker, C. & Stock, J. B. Carboxyl methylation of Ras-related proteins. Methods. Enzymol. 255, 65–82 (1995).

    CAS  PubMed  Google Scholar 

  84. Philips, M. R. et al. Carboxyl methylation of Ras-related proteins during signal transduction in neutrophils. Science 259, 977–980 (1993).

    CAS  PubMed  Google Scholar 

  85. Clarke, S., Vogel, J. P., Deschenes, R. J. & Stock, J. Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases. Proc. Natl Acad. Sci. USA 85, 4643–4647 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Chen, Z. Q., Ulsh, L. S., DuBois, G. & Shih, T. Y. Posttranslational processing of p21 ras proteins involves palmitylation of the C-terminal tetrapeptide containing cysteine-186. J. Virol. 56, 607–612 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Coats, S. G., Booden, M. A. & Buss, J. E. Transient palmitoylation supports H-Ras membrane binding but only partial biological activity. Biochemistry 38, 12926–12934 (1999).

    CAS  PubMed  Google Scholar 

  88. Kato, K., Der, C. J. & Buss, J. E. Prenoids and palmitate: lipids that control the biological activity of Ras proteins. Semin. Cancer Biol. 3, 179–188 (1992).

    CAS  PubMed  Google Scholar 

  89. Hancock, J. F., Cadwallader, K., Paterson, H. & Marshall, C. J. A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins. EMBO J. 10, 4033–4039 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Jackson, J. H., Li, J. W., Buss, J. E., Der, C. J. & Cochrane, C. G. Polylysine domain of K-ras 4B protein is crucial for malignant transformation. Proc. Natl Acad. Sci. USA 91, 12730–12734 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Niv, H., Gutman, O., Kloog, Y. & Henis, Y. I. Activated K-Ras and H-Ras display different interactions with saturable nonraft sites at the surface of live cells. J. Cell Biol. 157, 865–872 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Prior, I. A. et al. GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nature Cell. Biol. 3, 368–375 (2001).

    CAS  PubMed  Google Scholar 

  93. Prior, I. A., Muncke, C., Parton, R. G. & Hancock, J. F. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell. Biol. 160, 165–170 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Prior, I. A. & Hancock, J. F. Compartmentalization of Ras proteins. J. Cell. Sci. 114, 1603–1608 (2001).

    CAS  PubMed  Google Scholar 

  95. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931–943 (2000).

    CAS  PubMed  Google Scholar 

  96. Corbett, K. D. & Alber, T. The many faces of Ras: recognition of small GTP-binding proteins. Trends Biochem. Sci. 26, 710–716 (2001).

    CAS  PubMed  Google Scholar 

  97. Voice, J. K., Klemke, R. L., Le, A. & Jackson, J. H. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J. Biol. Chem. 274, 17164–17170 (1999).

    CAS  PubMed  Google Scholar 

  98. Kimmelman, A., Tolkacheva, T., Lorenzi, M. V., Osada, M. & Chan, A. M. Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene 15, 2675–2685 (1997).

    CAS  PubMed  Google Scholar 

  99. Quilliam, L. A. et al. M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J. Biol. Chem. 274, 23850–23857 (1999).

    CAS  PubMed  Google Scholar 

  100. York, R. D. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626 (1998).

    CAS  PubMed  Google Scholar 

  101. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).

    CAS  PubMed  Google Scholar 

  102. Yan, J., Roy, S., Apolloni, A., Lane, A. & Hancock, J. F. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J. Biol. Chem. 273, 24052–24056 (1998).

    CAS  PubMed  Google Scholar 

  103. Kimmelman, A. C., Osada, M. & Chan, A. M. R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 19, 2014–2022 (2000).

    CAS  PubMed  Google Scholar 

  104. Rose, D. M., Cardarelli, P. M., Cobb, R. R. & Ginsberg, M. H. Soluble VCAM-1 binding to α4 integrins is cell-type specific and activation dependent and is disrupted during apoptosis in T cells. Blood 95, 602–609 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

K.K., L.E.G., M.H. and F.L.C. are supported by postdoctoral fellowships from the University of California Tobacco-Related Disease Program, the American Cancer Society, the Danish Medical Research Council and the American Heart Association, respectively. Research in the Ginsberg laboratory is supported by the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Cell Biology, The Scripps Research Institute, La Jolla, 92037, California, USA

    Kayoko Kinbara, Lawrence E. Goldfinger, Fan-Li Chou & Mark H. Ginsberg

  2. Department of Biochemistry and Biophysics, University of California, San Francisco, 94143, California, USA

    Malene Hansen

Authors
  1. Kayoko Kinbara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lawrence E. Goldfinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Malene Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fan-Li Chou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark H. Ginsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark H. Ginsberg.

Related links

Related links

DATABASES

Interpro

Integrin α

Integrin β

LocusLink

H-ras

K-ras

N-ras

R-ras

R-ras2

R-ras3

RalA

RalB

Rheb

Rin

Rit

Swiss-Prot

Integrin α1

Integrin αIIb

Integrin α4

Integrin α5

Integrin α6

Integrin αM

Integrin αL

Integrin β1

Integrin β2

Integrin β3

Rap1A

Rap1B

Rap2A

Rap2B

Glossary

AFFINITY

The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex.

CAAX MOTIF

A carboxy-terminal tetrapeptide that is common to all Ras proteins and that directs a triplet of post-translational modifications.

HYPERVARIABLE DOMAIN

The carboxy-terminal 25 amino acids of H-, N- and K-ras proteins in which sequence homology is less than 15% between any two isoforms compared with 90–100% over the amino-terminal sequences.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

EOSINOPHIL

A type of white blood cell that has a bi-lobed nucleus and large cytoplasmic granules — containing hydrolytic enzymes — that stain readily with eosin.

SWITCH REGIONS

The structures of Ras proteins resolved in either GDP- or GTP-bound form showed that the conformational change resulting from nucleotide exchange is mostly confined to the loop L2-β2 (according to Ras structural nomenclature) and the β3/α2 regions, which are termed switch I and II regions.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

OPSONIZATION

The process by which microorganisms or other particulate material are rendered more susceptible to phagocytosis by coating with opsonin.

ADAPTOR PROTEIN

A protein that augments cellular responses by recruiting other proteins to a complex. Adaptor proteins usually contain several protein–protein interaction domains.

SH3 DOMAIN

(Src-homology-3 domain). Protein sequences of about 50 amino acids that recognize and bind sequences that are rich in proline.

EFFECTOR-LOOP-MUTANTS

Ras proteins with mutations in their effector-binding domains that abrogate their interactions with specific effectors.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

AVIDITY

The strength of binding, usually of multiple ligand–receptor complexes in aggregation.

MEGAKARYOCYTES

The source of blood platelets. The platelets are released by the megakaryocyte into the capillary sinuses. They are the largest cells in normal bone marrow.

Fab FRAGMENT

The antigen-binding fragment of an immunoglobulin molecule. It is used when multimerization of antibodies caused by their Fc domains is not desirable.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kinbara, K., Goldfinger, L., Hansen, M. et al. Ras GTPases: integrins' friends or foes?. Nat Rev Mol Cell Biol 4, 767–777 (2003). https://doi.org/10.1038/nrm1229

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1229

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing