Key Points
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Oncogenic mutations of Ras, which are found in human tumours, tumour cell lines and in carcinogen-induced experimental tumours, cause the hyper-activation of the Ras proteins.
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Ras proteins are GTPases that shuttle between the inactive GDP-bound and the active GTP-bound states. This nucleotide switching is regulated by guanine nucleotide exchange factors (GEFs), which favour the accumulation of RasGTP, and GTPase-activating proteins (GAPs), which facilitate GTP hydrolysis. Oncogenic mutations of Ras proteins are GAP-insensitive and are chronically active.
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Active GTP-bound Ras proteins activate signalling pathways by engaging partners called effectors. These effectors initiate a cascade of signal transduction events that control processes, such as gene expression, cell-cycle progression, membrane trafficking, motility and survival.
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De-regulated Ras signalling causes a series of congenital developmental disorders collectively known as cardio-facio-cutaneous syndromes. These diseases include neurofibromatosis type-1, Costello and Noonan syndromes, and are characterized by the accumulation of sporadic tumours, as well as skeletal, cardiac and visual abnormalities.
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The enzymes involved in the post-translational processing of Ras have been attractive drug targets for cancer therapy. Among them are the farnesyltransferase inhibitors (FTIs), which inhibit the critical farnesylation reaction.
Abstract
Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.
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References
DeFeo, D. et al. Analysis of two divergent rat genomic clones homologous to the transforming gene of Harvey murine sarcoma virus. Proc. Natl Acad. Sci. USA 78, 3328–3332 (1981).
Ellis, R. W., DeFeo, D., Furth, M. E. & Scolnick, E. M. Mouse cells contain two distinct ras gene mRNA species that can be translated into a p21 onc protein. Mol. Cell. Biol. 2, 1339–1345 (1982).
Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M. & Lowy, D. R. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 4848–4852 (1982).
Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).
Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474–478 (1982).
Der, C. J., Krontiris, T. G. & Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 3637–3640 (1982).
Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S. & Barbacid, M. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298, 343–347 (1982).
Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982).
Reddy, E. P., Reynolds, R. K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).
Taparowsky, E. et al. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300, 762–765 (1982).
Capon, D. J., Chen, E. Y., Levinson, A. D., Seeburg, P. H. & Goeddel, D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 302, 33–37 (1983). References 6–11 established that oncogenic activation of Ras is caused by point mutations of the endogenous gene.
Shimizu, K. et al. Three human transforming genes are related to the viral ras oncogenes. Proc. Natl Acad. Sci. USA 80, 2112–2116 (1983).
Hall, A., Marshall, C. J., Spurr, N. K. & Weiss, R. A. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature 303, 396–400 (1983).
Taparowsky, E., Shimizu, K., Goldfarb, M. & Wigler, M. Structure and activation of the human N-ras gene. Cell 34, 581–586 (1983).
Murray, M. J. et al. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Cell 33, 749–757 (1983).
Newbold, R. F. & Overell, R. W. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304, 648–651 (1983).
Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–602 (1983).
Ruley, H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304, 602–606 (1983). References 16–18 proposed the notion that multiple pathways are required for cellular transformation.
Rhim, J. S. et al. Neoplastic transformation of human epidermal keratinocytes by AD12-SV40 and Kirsten sarcoma viruses. Science 227, 1250–1252 (1985).
Yoakum, G. H. et al. Transformation of human bronchial epithelial cells transfected by Harvey ras oncogene. Science 227, 1174–1179 (1985).
Yancopoulos, G. D. et al. N-myc can cooperate with ras to transform normal cells in culture. Proc. Natl Acad. Sci. USA 82, 5455–5459 (1985).
Santos, E. et al. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 223, 661–664 (1984).
Nakano, H. et al. Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes. Proc. Natl Acad. Sci. USA 81, 71–75 (1984).
Hirai, H. et al. Activation of the c-K-ras oncogene in a human pancreas carcinoma. Biochem. Biophys. Res. Commun. 127, 168–174 (1985).
Hand, P. H. et al. Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon carcinomas. Proc. Natl Acad. Sci. USA 81, 5227–5231 (1984).
Fujita, J. et al. Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature 309, 464–466 (1984).
Gambke, C., Signer, E. & Moroni, C. Activation of N-ras gene in bone marrow cells from a patient with acute myeloblastic leukaemia. Nature 307, 476–478 (1984).
Gambke, C., Hall, A. & Moroni, C. Activation of an N-ras gene in acute myeloblastic leukemia through somatic mutation in the first exon. Proc. Natl Acad. Sci. USA 82, 879–882 (1985).
Bos, J. L. et al. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia. Nature 315, 726–730 (1985).
Janssen, J. W., Steenvoorden, A. C., Collard, J. G. & Nusse, R. Oncogene activation in human myeloid leukemia. Cancer Res. 45, 3262–3267 (1985).
Sklar, M. D. & Kitchingman, G. R. Isolation of activated ras transforming genes from two patients with Hodgkin's disease. Int. J. Radiat. Oncol. Biol. Phys. 11, 49–55 (1985).
Padua, R. A., Barrass, N. C. & Currie, G. A. Activation of N-ras in a human melanoma cell line. Mol. Cell. Biol. 5, 582–585 (1985).
Sukumar, S., Notario, V., Martin-Zanca, D. & Barbacid, M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature 306, 658–661 (1983).
Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983).
Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984). References 33–35 indicated that chemical carcinogenesis caused mutations of ras sequences.
Guerrero, I., Calzada, P., Mayer, A. & Pellicer, A. A molecular approach to leukemogenesis: mouse lymphomas contain an activated c-ras oncogene. Proc. Natl Acad. Sci. USA 81, 202–205 (1984).
Guerrero, I., Villasante, A., Corces, V. & Pellicer, A. Activation of a c-K-ras oncogene by somatic mutation in mouse lymphomas induced by γ radiation. Science 225, 1159–1162 (1984).
Mizuki, K., Nose, K., Okamoto, H., Tsuchida, N. & Hayashi, K. Amplification of c-Ki-ras gene and aberrant expression of c-myc in WI-38 cells transformed in vitro by γ-irradiation. Biochem. Biophys. Res. Commun. 128, 1037–1043 (1985).
Shih, T. Y., Papageorge, A. G., Stokes, P. E., Weeks, M. O. & Scolnick, E. M. Guanine nucleotide-binding and autophosphorylating activities associated with the p21src protein of Harvey murine sarcoma virus. Nature 287, 686–691 (1980).
Gilman, A. G. G proteins: transducers of receptor-generated signals. Annu. Rev. Biochem. 56, 615–649 (1987).
McGrath, J. P., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310, 644–649 (1984).
Gibbs, J. B., Sigal, I. S., Poe, M. & Scolnick, E. M. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc. Natl Acad. Sci. USA 81, 5704–5708 (1984).
Sweet, R. W. et al. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature 311, 273–275 (1984).
Clark, R., Wong, G., Arnheim, N., Nitecki, D. & McCormick, F. Antibodies specific for amino acid 12 of the ras oncogene product inhibit GTP binding. Proc. Natl Acad. Sci. USA 82, 5280–5284 (1985).
Der, C. J., Finkel, T. & Cooper, G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell 44, 167–176 (1986).
Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542–545 (1987). References 41–46 established that oncogenic mutation of ras affects its nucleotide cycle.
Shih, T. Y. et al. Identification of a precursor in the biosynthesis of the p21 transforming protein of harvey murine sarcoma virus. J. Virol. 42, 253–261 (1982).
Sefton, B. M., Trowbridge, I. S., Cooper, J. A. & Scolnick, E. M. The transforming proteins of Rous sarcoma virus, Harvey sarcoma virus and Abelson virus contain tightly bound lipid. Cell 31, 465–474 (1982).
Willumsen, B. M., Christensen, A., Hubbert, N. L., Papageorge, A. G. & Lowy, D. R. The p21 ras C-terminus is required for transformation and membrane association. Nature 310, 583–586 (1984).
Willumsen, B. M., Norris, K., Papageorge, A. G., Hubbert, N. L. & Lowy, D. R. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J. 3, 2581–2585 (1984).
Srivastava, S. K., Lacal, J. C., Reynolds, S. H. & Aaronson, S. A. Antibody of predetermined specificity to a carboxy-terminal region of H-ras gene products inhibits their guanine nucleotide-binding function. Mol. Cell. Biol. 5, 3316–3319 (1985).
Casey, P. J., Solski, P. A., Der, C. J. & Buss, J. E. p21ras is modified by a farnesyl isoprenoid. Proc. Natl Acad. Sci. USA 86, 8323–8327 (1989).
Schafer, W. R. et al. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science 245, 379–385 (1989).
Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J. & Brown, M. S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81–88 (1990).
Schaber, M. D. et al. Polyisoprenylation of Ras in vitro by a farnesyl-protein transferase. J. Biol. Chem. 265, 14701–14704 (1990).
Schafer, W. R. et al. Enzymatic coupling of cholesterol intermediates to a mating pheromone precursor and to the ras protein. Science 249, 1133–1139 (1990).
Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63, 133–139 (1990).
Kamata, T. & Feramisco, J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).
Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985).
Hagag, N., Halegoua, S. & Viola, M. Inhibition of growth factor-induced differentiation of PC12 cells by microinjection of antibody to ras p21. Nature 319, 680–682 (1986).
Campisi, J., Gray, H. E., Pardee, A. B., Dean, M. & Sonenshein, G. E. Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation. Cell 36, 241–247 (1984).
Samid, D., Schaff, Z., Chang, E. H. & Friedman, R. M. Interferon-induced modulation of human ras oncogene expression. Prog. Clin. Biol. Res. 192, 265–268 (1985).
Emanoil-Ravier, R. et al. Interferon-mediated regulation of myc and Ki-ras oncogene expression in long-term-treated murine viral transformed cells. J. Interferon Res. 5, 613–619 (1985).
Samid, D., Chang, E. H. & Friedman, R. M. Development of transformed phenotype induced by a human ras oncogene is inhibited by interferon. Biochem. Biophys. Res. Commun. 126, 509–516 (1985).
Korn, L. J., Siebel, C. W., McCormick, F. & Roth, R. A. Ras p21 as a potential mediator of insulin action in Xenopus oocytes. Science 236, 840–843 (1987).
Hurley, J. B., Simon, M. I., Teplow, D. B., Robishaw, J. D. & Gilman, A. G. Homologies between signal transducing G proteins and ras gene products. Science 226, 860–862 (1984).
Gibbs, J. B., Schaber, M. D., Allard, W. J., Sigal, I. S. & Scolnick, E. M. Purification of ras GTPase activating protein from bovine brain. Proc. Natl Acad. Sci. USA 85, 5026–5030 (1988).
Vogel, U. S. et al. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335, 90–93 (1988).
Trahey, M. et al. Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242, 1697–1700 (1988).
Molloy, C. J. et al. PDGF induction of tyrosine phosphorylation of GTPase activating protein. Nature 342, 711–714 (1989).
Xu, G. F. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).
Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).
Martin, G. A. et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849 (1990).
Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).
Robinson, L. C., Gibbs, J. B., Marshall, M. S., Sigal, I. S. & Tatchell, K. CDC25: a component of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235, 1218–1221 (1987).
Broek, D. et al. The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell 48, 789–799 (1987).
Wolfman, A. & Macara, I. G. A cytosolic protein catalyzes the release of GDP from p21ras. Science 248, 67–69 (1990).
Downward, J., Riehl, R., Wu, L. & Weinberg, R. A. Identification of a nucleotide exchange-promoting activity for p21ras. Proc. Natl Acad. Sci. USA 87, 5998–6002 (1990).
West, M., Kung, H. F. & Kamata, T. A novel membrane factor stimulates guanine nucleotide exchange reaction of ras proteins. FEBS Lett. 259, 245–248 (1990).
Wei, W. et al. Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 89, 7100–7104 (1992).
Shou, C., Farnsworth, C. L., Neel, B. G. & Feig, L. A. Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature 358, 351–354 (1992).
Bowtell, D., Fu, P., Simon, M. & Senior, P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc. Natl Acad. Sci. USA 89, 6511–6515 (1992).
Gale, N. W., Kaplan, S., Lowenstein, E. J., Schlessinger, J. & Bar-Sagi, D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363, 88–92 (1993).
Li, N. et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363, 85–88 (1993).
Rozakis-Adcock, M., Fernley, R., Wade, J., Pawson, T. & Bowtell, D. The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363, 83–85 (1993).
Egan, S. E. et al. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363, 45–51 (1993).
Buday, L. & Downward, J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73, 611–620 (1993).
Bernards, A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim. Biophys. Acta 1603, 47–82 (2003).
Geyer, M. & Wittinghofer, A. GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins. Curr. Opin. Struct. Biol. 7, 786–792 (1997).
Tucker, J. et al. Expression of p21 proteins in Escherichia coli and stereochemistry of the nucleotide-binding site. EMBO J. 5, 1351–1358 (1986).
Itoh, H. et al. Molecular cloning and sequence determination of cDNAs for α subunits of the guanine nucleotide-binding proteins Gs, Gi, and Go from rat brain. Proc. Natl Acad. Sci. USA 83, 3776–3780 (1986).
Clanton, D. J., Hattori, S. & Shih, T. Y. Mutations of the ras gene product p21 that abolish guanine nucleotide binding. Proc. Natl Acad. Sci. USA 83, 5076–5080 (1986).
Der, C. J., Pan, B. T. & Cooper, G. M. rasH mutants deficient in GTP binding. Mol. Cell. Biol. 6, 3291–3294 (1986).
Lacal, J. C., Anderson, P. S. & Aaronson, S. A. Deletion mutants of Harvey ras p21 protein reveal the absolute requirement of at least two distant regions for GTP-binding and transforming activities. EMBO J. 5, 679–687 (1986).
Sigal, I. S., Gibbs, J. B., D'Alonzo, J. S. & Scolnick, E. M. Identification of effector residues and a neutralizing epitope of Ha-ras-encoded p21. Proc. Natl Acad. Sci. USA 83, 4725–4729 (1986).
Stone, J. C., Vass, W. C., Willumsen, B. M. & Lowy, D. R. p21-ras effector domain mutants constructed by “cassette” mutagenesis. Mol. Cell. Biol. 8, 3565–3569 (1988).
Pai, E. F. et al. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341, 209–214 (1989).
Brunger, A. T. et al. Crystal structure of an active form of RAS protein, a complex of a GTP analog and the HRAS p21 catalytic domain. Proc. Natl Acad. Sci. USA 87, 4849–4853 (1990).
Milburn, M. V. et al. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247, 939–945 (1990).
Schlichting, I. et al. Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature 345, 309–315 (1990).
Tong, L. A. et al. Structural differences between a ras oncogene protein and the normal protein. Nature 337, 90–93 (1989).
Krengel, U. et al. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell 62, 539–548 (1990).
Scheffzek, K. et al. The Ras–RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333–338 (1997).
Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D. & Kuriyan, J. The structural basis of the activation of Ras by Sos. Nature 394, 337–343 (1998). References 97–104 described the structural details of Ras activation.
Bar-Sagi, D. & Feramisco, J. R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233, 1061–1068 (1986).
Backer, J. M. & Weinstein, I. B. p21 ras proteins and guanine nucleotides modulate the phosphorylation of 36- and 17-kilodalton mitochondria-associated proteins. Proc. Natl Acad. Sci. USA 83, 6357–6361 (1986).
Hegde, A. N. & Das, M. R. ras proteins enhance the phosphorylation of a 38 kDa protein (p38) in rat liver plasma membrane. FEBS Lett. 217, 74–80 (1987).
Lacal, J. C. et al. Rapid stimulation of diacylglycerol production in Xenopus oocytes by microinjection of H-ras p21. Science 238, 533–536 (1987).
Lacal, J. C., Moscat, J. & Aaronson, S. A. Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. Nature 330, 269–272 (1987).
Wolfman, A. & Macara, I. G. Elevated levels of diacylglycerol and decreased phorbol ester sensitivity in ras-transformed fibroblasts. Nature 325, 359–361 (1987).
Fleischman, L. F., Chahwala, S. B. & Cantley, L. ras-transformed cells: altered levels of phosphatidylinositol-4,5-bisphosphate and catabolites. Science 231, 407–410 (1986).
Lacal, J. C., Fleming, T. P., Warren, B. S., Blumberg, P. M. & Aaronson, S. A. Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product. Mol. Cell. Biol. 7, 4146–4149 (1987).
Huang, M. et al. Enhancement of inositol phospholipid metabolism and activation of protein kinase C in ras-transformed rat fibroblasts. J. Biol. Chem. 263, 17975–17980 (1988).
Fukami, K. et al. Antibody to phosphatidylinositol 4,5-bisphosphate inhibits oncogene-induced mitogenesis. Proc. Natl Acad. Sci. USA 85, 9057–9061 (1988).
Moodie, S. A., Willumsen, B. M., Weber, M. J. & Wolfman, A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260, 1658–1661 (1993).
Warne, P. H., Viciana, P. R. & Downward, J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364, 352–355 (1993).
Zhang, X. F. et al. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364, 308–313 (1993).
Vojtek, A. B., Hollenberg, S. M. & Cooper, J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74, 205–214 (1993). References 115–118 described the physical and functional coupling of Ras to the Raf–MAPK effector pathway.
Wood, K. W., Sarnecki, C., Roberts, T. M. & Blenis, J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68, 1041–1050 (1992).
Leevers, S. J. & Marshall, C. J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 11, 569–574 (1992).
Leevers, S. J., Paterson, H. F. & Marshall, C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369, 411–414 (1994).
Stokoe, D., Macdonald, S. G., Cadwallader, K., Symons, M. & Hancock, J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science 264, 1463–1467 (1994).
Khosravi-Far, R., Solski, P. A., Clark, G. J., Kinch, M. S. & Der, C. J. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol. Cell. Biol. 15, 6443–6453 (1995).
White, M. A. et al. Multiple Ras functions can contribute to mammalian cell transformation. Cell 80, 533–541 (1995).
Rajagopalan, H. et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934 (2002).
Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).
Hofer, F., Fields, S., Schneider, C. & Martin, G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc. Natl Acad. Sci. USA 91, 11089–11093 (1994).
Kikuchi, A., Demo, S. D., Ye, Z. H., Chen, Y. W. & Williams, L. T. ralGDS family members interact with the effector loop of ras p21. Mol. Cell. Biol. 14, 7483–7491 (1994).
Spaargaren, M. & Bischoff, J. R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc. Natl Acad. Sci. USA 91, 12609–12613 (1994).
Rodriguez-Viciana, P. et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457–467 (1997).
Marte, B. M. & Downward, J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem. Sci. 22, 355–358 (1997).
Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16, 2783–2793 (1997).
Mayo, M. W. et al. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278, 1812–1815 (1997).
White, M. A., Vale, T., Camonis, J. H., Schaefer, E. & Wigler, M. H. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J. Biol. Chem. 271, 16439–16442 (1996).
Urano, T., Emkey, R. & Feig, L. A. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 15, 810–816 (1996).
Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).
Chien, Y. & White, M. A. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 4, 800–806 (2003).
Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase Cɛ: a novel Ras effector. EMBO J. 20, 743–754 (2001).
Song, C. et al. Regulation of a novel human phospholipase, C, PLCɛ, through membrane targeting by Ras. J. Biol. Chem. 276, 2752–2757 (2001).
Lopez, I., Mak, E. C., Ding, J., Hamm, H. E. & Lomasney, J. W. A novel bifunctional phospholipase C that is regulated by Gα12 and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276, 2758–2765 (2001).
Lambert, J. M. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol. 4, 621–625 (2002).
Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002).
Bai, Y. et al. Crucial role of phospholipase Cɛ in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808–8810 (2004).
Gupta, S. et al. Binding of Ras to phosphoinositide 3-kinase p110α is required for Ras-driven tumorigenesis in mice. Cell 129, 957–968 (2007).
Gonzalez-Garcia, A. et al. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219–226 (2005).
Kuriyama, M. et al. Identification of AF-6 and canoe as putative targets for Ras. J. Biol. Chem. 271, 607–610 (1996).
Ponting, C. P. & Benjamin, D. R. A novel family of Ras-binding domains. Trends Biochem. Sci. 21, 422–425 (1996).
Mandai, K. et al. Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction. J. Cell Biol. 139, 517–528 (1997).
Han, L. & Colicelli, J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol. Cell. Biol. 15, 1318–1323 (1995).
Tall, G. G., Barbieri, M. A., Stahl, P. D. & Horazdovsky, B. F. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev. Cell 1, 73–82 (2001).
Milstein, M. et al. RIN1 is a breast tumor suppressor gene. Cancer Res. 67, 11510–11516 (2007).
Vavvas, D., Li, X., Avruch, J. & Zhang, X. F. Identification of Nore1 as a potential Ras effector. J. Biol. Chem. 273, 5439–5442 (1998).
Khokhlatchev, A. et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253–265 (2002).
Vos, M. D., Martinez, A., Ellis, C. A., Vallecorsa, T. & Clark, G. J. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J. Biol. Chem. 278, 21938–21943 (2003).
Vos, M. D. et al. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J. Biol. Chem. 278, 28045–28051 (2003).
Tommasi, S. et al. Tumor susceptibility of Rassf1a knockout mice. Cancer Res. 65, 92–98 (2005).
Leon, J., Guerrero, I. & Pellicer, A. Differential expression of the ras gene family in mice. Mol. Cell. Biol. 7, 1535–1540 (1987).
Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).
Koera, K. et al. K-ras is essential for the development of the mouse embryo. Oncogene 15, 1151–1159 (1997).
Esteban, L. M. et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol. 21, 1444–1452 (2001).
Umanoff, H., Edelmann, W., Pellicer, A. & Kucherlapati, R. The murine N-ras gene is not essential for growth and development. Proc. Natl Acad. Sci. USA 92, 1709–1713 (1995).
Potenza, N. et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 6, 432–437 (2005).
Fiorucci, G. & Hall, A. All three human ras genes are expressed in a wide range of tissues. Biochim. Biophys. Acta 950, 81–83 (1988).
Bivona, T. G. et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481–493 (2006).
Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002).
Matallanas, D. et al. Distinct utilization of effectors and biological outcomes resulting from site-specific Ras activation: Ras functions in lipid rafts and Golgi complex are dispensable for proliferation and transformation. Mol. Cell. Biol. 26, 100–116 (2006).
Augsten, M. et al. Live-cell imaging of endogenous Ras-GTP illustrates predominant Ras activation at the plasma membrane. EMBO Rep. 7, 46–51 (2006).
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).
Cawthon, R. M. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193–201 (1990).
Marchuk, D. A. et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11, 931–940 (1991).
Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192 (1990).
Rodriguez-Viciana, P. et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287–1290 (2006).
Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593–604 (2001).
Brannan, C. I. et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994).
Gitler, A. D. et al. Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia. Pediatr. Res. 55, 581–584 (2004).
Ismat, F. A., Xu, J., Lu, M. M. & Epstein, J. A. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. J. Clin. Invest. 116, 2378–2384 (2006).
Mohi, M. G. & Neel, B. G. The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17, 23–30 (2007).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465–468 (2001).
Keilhack, H., David, F. S., McGregor, M., Cantley, L. C. & Neel, B. G. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J. Biol. Chem. 280, 30984–30993 (2005).
Tartaglia, M. & Gelb, B. D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).
Chan, R. J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).
Araki, T. et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nature Med. 10, 849–857 (2004).
Flotho, C. et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13, 32–37 (1999).
Gorlin, R. J., Anderson, R. C. & Moller, J. H. The leopard (multiple lentigines) syndrome revisited. Laryngoscope 81, 1674–1681 (1971).
Roberts, A. et al. The cardiofaciocutaneous syndrome. J. Med. Genet. 43, 833–842 (2006).
Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71–75 (1984).
Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nature Genet. 38, 331–336 (2006).
Roberts, A. E. et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genet. 39, 70–74 (2007).
Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995). One of the initial reports suggesting the feasibility of the FTI approach in vivo.
James, G. L., Goldstein, J. L. & Brown, M. S. Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J. Biol. Chem. 270, 6221–6226 (1995).
Sepp-Lorenzino, L. et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 55, 5302–5309 (1995).
Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res. 55, 4243–4247 (1995).
Mangues, R. et al. Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res. 58, 1253–1259 (1998).
Lebowitz, P. F., Casey, P. J., Prendergast, G. C. & Thissen, J. A. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J. Biol. Chem. 272, 15591–15594 (1997).
Basso, A. D. et al. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280, 31101–31108 (2005).
Liu, A., Du, W., Liu, J. P., Jessell, T. M. & Prendergast, G. C. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105–6113 (2000).
Ashar, H. R. et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J. Biol. Chem. 275, 30451–30457 (2000).
Hrycyna, C. A., Sapperstein, S. K., Clarke, S. & Michaelis, S. The Saccharomyces cerevisiae STE14 gene encodes a methyltransferase that mediates C-terminal methylation of a-factor and RAS proteins. EMBO J. 10, 1699–1709 (1991).
Kato, K. et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc. Natl Acad. Sci. USA 89, 6403–6407 (1992).
Bergo, M. O. et al. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol. 22, 171–181 (2002).
Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004).
Winter-Vann, A. M. et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc. Natl Acad. Sci. USA 100, 6529–6534 (2003).
Winter-Vann, A. M. et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc. Natl Acad. Sci. USA 102, 4336–4341 (2005).
Mukhopadhyay, T., Tainsky, M., Cavender, A. C. & Roth, J. A. Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res. 51, 1744–1748 (1991).
Funato, T., Ishii, T., Kambe, M., Scanlon, K. J. & Sasaki, T. Anti-K-ras ribozyme induces growth inhibition and increased chemosensitivity in human colon cancer cells. Cancer Gene Ther. 7, 495–500 (2000).
Zhang, Y. A., Nemunaitis, J., Scanlon, K. J. & Tong, A. W. Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. Gene Ther. 7, 2041–2050 (2000).
Kijima, H. et al. Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer. Int. J. Oncol. 24, 559–564 (2004).
Coffey, M. C., Strong, J. E., Forsyth, P. A. & Lee, P. W. Reovirus therapy of tumors with activated Ras pathway. Science 282, 1332–1334 (1998).
Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 17, 3351–3362 (1998).
Bollag, G., Freeman, S., Lyons, J. F. & Post, L. E. Raf pathway inhibitors in oncology. Curr. Opin. Investig. Drugs 4, 1436–1441 (2003).
Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810–816 (1999).
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). Indicated that forced overexpression of Ras in primary cells promoted growth arrest through the p53 and p16 pathways.
Wei, W., Jobling, W. A., Chen, W., Hahn, W. C. & Sedivy, J. M. Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol. Cell. Biol. 23, 2859–2870 (2003).
Voorhoeve, P. M. & Agami, R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell 4, 311–319 (2003).
Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).
Benanti, J. A. & Galloway, D. A. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24, 2842–2852 (2004).
Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).
Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131–144 (2003).
Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999).
McCubrey, J. A., Lahair, M. M. & Franklin, R. A. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid. Redox Signal 8, 1775–1789 (2006).
Sun, P. et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295–308 (2007).
Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J. & Der, C. J. Increasing complexity of Ras signaling. Oncogene 17, 1395–1413 (1998).
Wright, L. P. & Philips, M. R. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J. Lipid Res. 47, 883–891 (2006).
Whyte, D. B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).
Choy, E. et al. Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69–80 (1999).
Apolloni, A., Prior, I. A., Lindsay, M., Parton, R. G. & Hancock, J. F. H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol. 20, 2475–2487 (2000).
Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).
Rocks, O. et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307, 1746–1752 (2005).
Jura, N., Scotto-Lavino, E., Sobczyk, A. & Bar-Sagi, D. Differential modification of Ras proteins by ubiquitination. Mol. Cell 21, 679–687 (2006).
Acknowledgements
We thank C. Der for comments on the manuscript and G. Bell for help in structural configurations. The authors' research is supported, in part, by the Breast Cancer Research Foundation (R.A.W), National Institues of Health (NIH) P01 CA08111 (R.A.W.), NIH U54 CA12515 (R.A.W.), NIH SPORE P50 CA089393 (R.A.W.), Susan Komen Breast Cancer Foundation (A.E.K.), Harvard Specialized Program for Research Excellence (A.E.K.), Whitehead Institute-Genzyme fellowship (A.E.K.) and the Ludwig Center for Molecular Oncology at Massachusetts Institue of Technology, USA.
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DATABASES
FirstGlance in Jmol (3D structures)
Interpro
OMIM
neurofibromatosis type-1 syndrome
FURTHER INFORMATION
Glossary
- Rous sarcoma virus
-
(RSV). A retrovirus that was discovered in 1916 by Peyton Rous by injecting a cell-free extract of chicken tumour into healthy chickens. The extract was found to induce oncogenesis in Plymouth Rock chickens.
- G proteins
-
A family of proteins involved in second messenger cascades. They function as molecular switches, alternating between an inactive GDP-bound and active GTP-bound state.
- GTPase-activating protein
-
(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP bound) to inactive (GDP bound).
- Guanine nucleotide-exchange factor
-
(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.
- Anoikis
-
The induction of programmed cell death by the detachment of cells from the extracellular matrix.
- Lipid raft
-
A membrane microdomain that is enriched in cholesterol, sphingolipids and lipid-modified proteins, such as glycosyl phosphatidylinositol (GPI)-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.
- Cardio-facio-cutaneous diseases
-
Congenital developmental disorders caused by disregulated Ras signalling. These diseases are characterized by the accumulation of sporadic tumours as well as skeletal, cardiac and visual abnormalities.
- Neural crest
-
A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.
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Karnoub, A., Weinberg, R. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9, 517–531 (2008). https://doi.org/10.1038/nrm2438
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DOI: https://doi.org/10.1038/nrm2438
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