RAS proteins are molecular switches that regulate a wide range of signalling pathways by engaging effectors on cellular membranes. They are themselves regulated by various post-translational modifications (PTMs).
RAS proteins associate with membranes by virtue of a series of constitutive PTMs of their carboxy-terminal CAAX sequence. These PTMs include prenylation, proteolysis and carboxyl methylation.
Membrane association and trafficking of all RAS isoforms other than KRAS4B are also regulated by the reversible palmitoylation of Cys residues in the C-terminal hypervariable regions of the proteins.
Cis–trans isomerization of a peptidyl-prolyl bond adjacent to a palmitate in HRAS acts as a molecular timer that regulates depalmitoylation and retrograde trafficking.
Phosphorylation of KRAS4B in its polybasic region allows this protein to dissociate from the plasma membrane through a mechanism known as the farnesyl–electrostatic switch.
Monoubiquitylation and diubiquitylation of HRAS regulate its association with endosomes, and monoubiquitylation of KRAS4B enhances its activation.
S-nitrosylation of Cys118 of RAS promotes guanine nucleotide exchange.
Toxins produced by Pseudomonas aeruginosa and Clostridium sordelli ADP-ribosylate and monglucosylate RAS, respectively, leading to diminished signalling.
RAS proteins are monomeric GTPases that act as binary molecular switches to regulate a wide range of cellular processes. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which regulate the activation state of RAS without covalently modifying it. By contrast, post-translational modifications (PTMs) of RAS proteins direct them to various cellular membranes and, in some cases, modulate GTP–GDP exchange. Important RAS PTMs include the constitutive and irreversible remodelling of its carboxy-terminal CAAX motif by farnesylation, proteolysis and methylation, reversible palmitoylation, and conditional modifications, including phosphorylation, peptidyl-prolyl isomerisation, monoubiquitylation, diubiquitylation, nitrosylation, ADP ribosylation and glucosylation.
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Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nature Rev. Cancer 3, 459–465 (2003).
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).
Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37, 1038–1040 (2005).
Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nature Genet. 38, 331–336 (2006).
Niihori, T. et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genet. 38, 294–296 (2006).
Cox, A. D. & Der, C. J. Ras history: the saga continues. Small Gtpases 1, 2–27 (2011).
Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nature Genet. 40, 600–608 (2008). Demonstrates significant biological differences in vivo between RAS isoforms.
Choy, E. et al. Endomembrane trafficking of Ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69–80 (1999). Establishes the involvement of the endomembrane in RAS processing.
Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002). Reports RAS signalling from endomembranes for the first time.
Bivona, T. G. et al. Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003).
Casar, B. et al. Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol. Cell. Biol. 29, 1338–1353 (2009).
Vigil, D., Cherfils, J., Rossman, K. L. & Der, C. J. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nature Rev. Cancer 10, 842–857 (2010).
Barbacid, M. ras genes. Annu. Rev. Biochem. 56, 779–827 (1987).
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).
Zhao, C., Du, G., Skowronek, K., Frohman, M. A. & Bar-Sagi, D. Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nature Cell Biol. 9, 706–712 (2007).
Yadav, K. K. & Bar-Sagi, D. Allosteric gating of Son of sevenless activity by the histone domain. Proc. Natl Acad. Sci. USA 107, 3436–3440 (2010).
Chung, H. H., Benson, D. R., Cornish, V. W. & Schultz, P. G. Probing the role of loop 2 in Ras function with unnatural amino acids. Proc. Natl Acad. Sci. USA 90, 10145–10149 (1993).
Rojas, J. & Santos, E. in Proteins and Cell Regulation Vol. 4: RAS Family GTPases (Ed. Der, C.) 15–43 (Springer, 2006).
Ahmadian, M. R., Stege, P., Scheffzek, K. & Wittinghofer, A. Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras. Nature Struct. Biol. 4, 686–689 (1997).
Scheffzek, K. et al. The Ras–RasGAP complex: structural basis for GTPase activation and its loss in oncogenic mutants. Science 277, 333–339 (1997).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Dickson, B., Sprenger, F., Morrison, D. & Hafen, E. Raf functions downstream of Ras1 in the Sevenless signal transduction pathway. Nature 360, 600–603 (1992).
Han, M., Golden, A., Han, Y. & Sternberg, P. W. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 363, 133–140 (1993).
Van Aelst, L., Barr, M., Marcus, S., Polverino, A. & Wigler, M. Complex formation between RAS and RAF and other protein kinases. Proc. Natl Acad. Sci. USA 90, 6213–6217 (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).
Moodie, S. A., Willumsen, B. M., Weber, M. J. & Wolfman, A. Complexes of Ras.GTP with RAf-1 and mitogen-activated protein kinase. Science 260, 1658–1661 (1993).
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006). Reveals distinct biological outcomes from RAS–MAPK signalling on different subcellular compartments.
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
D'Adamo, D. R., Novick, S., Kahn, J. M., Leonardi, P. & Pellicer, A. rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral. Oncogene 14, 1295–1305 (1997).
Gonzalez-Garcia, A. et al. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219–226 (2005).
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).
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).
Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase C(epsilon): a novel Ras effector. EMBO J. 20, 743–754 (2001).
Bai, Y. et al. Crucial role of phospholipase Cepsilon in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808–8810 (2004).
Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002).
Morrison, D. K. & Cutler, R. E. The complexity of Raf-1 regulation. Curr. Opin. Cell Biol. 9, 174–179 (1997).
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).
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).
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).
Seabra, M. C., Reiss, Y., Casey, P. J., Brown, M. S. & Goldstein, J. L. Protein farnesyltransferase and geranylgeranyltransferase share a common α subunit. Cell 65, 429–434 (1991).
Reid, T. S., Terry, K. L., Casey, P. J. & Beese, L. S. Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J. Mol. Biol. 343, 417–433 (2004).
Hoffman, G. R., Nassar, N. & Cerione, R. A. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100, 345–356 (2000).
Silvius, J. R. & l'Heureux, F. Fluorimetric evaluation of the affinities of isoprenylated peptides for lipid bilayers. Biochemistry 33, 3014–3022 (1994).
Ismail, S. A. et al. Regulation of a GDI-like transport system for farnesylated cargo by Arl2/3-GTP. Nature Chem. Biol. 7, 942–949 (2011).
Chandra, A. et al. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nature Cell Biol. 18 Dec 2011 (doi:10.1038/ncb2394).
Boyartchuk, V. L., Ashby, M. N. & Rine, J. Modulation of Ras and a-factor function by carboxyl-terminal proteolysis. Science 275, 1796–1800 (1997).
Dai, Q. et al. Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum. J. Biol. Chem. 273, 15030–15034 (1998).
Berg, T. J. et al. Splice variants of SmgGDS control small GTPase prenylation and membrane localization. J. Biol. Chem. 285, 35255–35266 (2010).
Kohl, N. E. et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260, 1934–1937 (1993).
Lerner, E. C. et al. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras–Raf complexes. J. Biol. Chem. 270, 26802–26806 (1995).
Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to loacalize p21ras to the plasma membrane. Cell 63, 133–139 (1990). Describes the polybasic sequence of KRAS as an alternative membrane-targeting motif.
Resh, M. D. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim. Biophys. Acta 1451, 1–16 (1999).
Buss, J. E. & Sefton, B. M. Direct identification of palmitic acid as the lipid attached to p21ras. Mol. Cell. Biol. 6, 116–122 (1986).
Hancock, J. F., Magee, A. I., Childs, J. E. & Marshall, C. J. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57, 1167–1177 (1989). Demonstrates that RAS proteins are isoprenylated.
Laude, A. J. & Prior, I. A. Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J. Cell Sci. 121, 421–427 (2008).
Magee, A. I., Gutierrez, L., McKay, I. A., Marshall, C. J. & Hall, A. Dynamic fatty acylation of p21N-ras. EMBO J. 6, 3353–3357 (1987). Shows that palmitoylation of RAS is reversible.
Swarthout, J. T. et al. DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J. Biol. Chem. 280, 31141–31148 (2005). Characterizes a PAT that modifies RAS.
Lobo, S., Greentree, W. K., Linder, M. E. & Deschenes, R. J. Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. J. Biol. Chem. 277, 41268–41273 (2002).
Mitchell, D. A., Vasudevan, A., Linder, M. E. & Deschenes, R. J. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J. Lipid Res. 47, 1118–1127 (2006).
Rocks, O. et al. The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins. Cell 141, 458–471 (2010).
Mitchell, D. A., Farh, L., Marshall, T. K. & Deschenes, R. J. A polybasic domain allows nonprenylated Ras proteins to function in Saccharomyces cerevisiae. J. Biol. Chem. 269, 21540–21546 (1994).
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).
Shahinian, S. & Silvius, J. R. Doubly-lipid-modified protein sequence motifs exhibit long-lived anchorage to lipid bilayer membranes. Biochemistry 34, 3813–3822 (1995).
Schroeder, H. et al. S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts. Biochemistry 36, 13102–13109 (1997).
Silvius, J. R., Bhagatji, P., Leventis, R. & Terrone, D. K-ras4B and prenylated proteins lacking “second signals” associate dynamically with cellular membranes. Mol. Biol. Cell 17, 192–202 (2006). Demonstrates that the association of KRAS with the plasma membrane is reversible and highly dynamic.
Rocks, O. et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307, 1746–1752 (2005).
Goodwin, J. S. et al. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway. J. Cell Biol. 170, 261–272 (2005). References 71 and 72 establish that the palmitoylation–depalmitoylation of NRAS and HRAS mediates a cycle of transport between the Golgi and plasma membrane.
Mor, A. et al. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nature Cell Biol. 9, 713–719 (2007).
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).
Mor, A. & Philips, M. R. Compartmentalized Ras/MAPK signaling. Annu. Rev. Immunol. 24, 771–800 (2006).
Baker, T. L., Zheng, H., Walker, J., Coloff, J. L. & Buss, J. E. Distinct rates of palmitate turnover on membrane-bound cellular and oncogenic H-ras. J. Biol. Chem. 278, 19292–19300 (2003).
Dekker, F. J. et al. Small-molecule inhibition of APT1 affects Ras localization and signaling. Nature Chem. Biol. 6, 449–456 (2010).
Zeidman, R., Jackson, C. S. & Magee, A. I. Protein acyl thioesterases. Mol. Membr. Biol. 26, 32–41 (2009).
Ahearn, I. M. et al. FKBP12 binds to acylated H-ras and promotes depalmitoylation. Mol. Cell 41, 173–185 (2011). Shows that cis – trans peptidyl-prolyl isomerization in the C terminus of HRAS regulates depalmitoylation.
Lu, K. P., Finn, G., Lee, T. H. & Nicholson, L. K. Prolyl cis–trans isomerization as a molecular timer. Nature Chem. Biol. 3, 619–629 (2007).
Ballester, R., Furth, M. E. & Rosen, O. M. Phorbol ester- and protein kinase C-mediated phosphorylation of the cellular Kirsten ras gene product. J. Biol. Chem. 262, 2688–2695 (1987).
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). Reports that phosphorylation of KRAS at Ser181 regulates its subcellular localization and leads to cell death.
McLaughlin, S. & Aderem, A. The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions. Trends Biochem. Sci. 20, 272–276 (1995).
Madigan, J. P. et al. Regulation of Rnd3 localization and function by protein kinase C α-mediated phosphorylation. Biochem. J. 424, 153–161 (2009).
Kashatus, D. F. et al. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature Cell Biol. 13, 1108–1115 (2011).
Fivaz, M. & Meyer, T. Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulin. J. Cell Biol. 170, 429–441 (2005).
Jura, N., Scotto-Lavino, E., Sobczyk, A. & Bar-Sagi, D. Differential modification of Ras proteins by ubiquitination. Mol. Cell 21, 679–687 (2006). Establishes monoubiquitylation and diubiquitylation of HRAS and shows the effects of this PTM on the localization on endosomes.
Sasaki, A. T. et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci. Signal. 4, ra13 (2010).
Xu, L., Lubkov, V., Taylor, L. J. & Bar-Sagi, D. Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr. Biol. 20, 1372–1377 (2010). Identifies RABEX5 as the E3 ubiquitin ligase that modifies RAS in a reaction that requires the RAS effector RIN1, suggesting feedback between this modification and signalling.
Lander, H. M., Ogiste, J. S., Teng, K. K. & Novogrodsky, A. p21ras as a common signaling target of reactive free radicals and cellular redox stress. J. Biol. Chem. 270, 21195–21198 (1995).
Lander, H. M. et al. Redox regulation of cell signalling. Nature 381, 380–381 (1996). Reveals, through a mass spectroscopy analysis, that Cys118 is the site of redox regulation of RAS and that S -nitrosylation of this Cys promotes guanine nucleotide exchange.
Heo, J. & Campbell, S. L. Mechanism of p21Ras S-nitrosylation and kinetics of nitric oxide-mediated guanine nucleotide exchange. Biochemistry 43, 2314–2322 (2004).
Lander, H. M., Ogiste, J. S., Pearce, S. F., Levi, R. & Novogrodsky, A. Nitric oxide-stimulated guanine nucleotide exchange on p21ras. J. Biol. Chem. 270, 7017–7020 (1995).
Williams, J. G., Pappu, K. & Campbell, S. L. Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proc. Natl Acad. Sci. USA 100, 6376–6381 (2003).
Aktories, K., Schmidt, G. & Just, I. Rho GTPases as targets of bacterial protein toxins. Biol. Chem. 381, 421–426 (2000).
Ganesan, A. K., Vincent, T. S., Olson, J. C. & Barbieri, J. T. Pseudomonas aeruginosa exoenzyme S disrupts Ras-mediated signal transduction by inhibiting guanine nucleotide exchange factor-catalyzed nucleotide exchange. J. Biol. Chem. 274, 21823–21829 (1999).
Just, I., Selzer, J., Hofmann, F., Green, G. A. & Aktories, K. Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation. J. Biol. Chem. 271, 10149–10153 (1996). Reports, for the first time, a bacterial toxin that inactivates RAS by PTM.
Herrmann, C., Ahmadian, M. R., Hofmann, F. & Just, I. Functional consequences of monoglucosylation of Ha-Ras at effector domain amino acid threonine 35. J. Biol. Chem. 273, 16134–16139 (1998).
Schmidt, W. K., Tam, A., Fujimura-Kamada, K. & Michaelis, S. Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage. Proc. Natl Acad. Sci. USA 95, 11175–11180 (1998).
Wright, L. P. et al. Topology of mammalian isoprenylcysteine carboxyl methyltransferase determined in live cells with a fluorescent probe. Mol. Cell. Biol. 29, 1826–1833 (2009).
Lane, K. T. & Beese, L. S. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J. Lipid Res. 47, 681–699 (2006).
Nancy, V., Callebaut, I., El Marjou, A. & de Gunzburg, J. The δ subunit of retinal rod cGMP phosphodiesterase regulates the membrane association of Ras and Rap GTPases. J. Biol. Chem. 277, 15076–15084 (2002).
Figueroa, C., Taylor, J. & Vojtek, A. B. Prenylated Rab acceptor protein is a receptor for prenylated small GTPases. J. Biol. Chem. 276, 28219–28225 (2001).
Paz, A., Haklai, R., Elad-Sfadia, G., Ballan, E. & Kloog, Y. Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation. Oncogene 20, 7486–7493 (2001).
Fehrenbacher, N., Bar-Sagi, D. & Philips, M. Ras/MAPK signaling from endomembranes. Mol. Oncol. 3, 297–307 (2009).
Di Fiore, P. P. & De Camilli, P. Endocytosis and signaling: an inseparable partnership. Cell 106, 1–4 (2001).
Zoncu, R. et al. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136, 1110–1121 (2009).
Misaki, R. et al. Palmitoylated Ras proteins traffic through recycling endosomes to the plasma membrane during exocytosis. J. Cell Biol. 191, 23–29 (2010).
Omerovic, J., Hammond, D. E., Clague, M. J. & Prior, I. A. Ras isoform abundance and signalling in human cancer cell lines. Oncogene 27, 2754–2762 (2008).
Roy, S., Wyse, B. & Hancock, J. F. H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Mol. Cell. Biol. 22, 5128–5140 (2002).
Lu, A. et al. A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes. J. Cell Biol. 184, 863–879 (2009).
Henis, Y. I., Hancock, J. F. & Prior, I. A. Ras acylation, compartmentalization and signaling nanoclusters. Mol. Membr. Biol. 26, 80–92 (2009).
Edidin, M. The state of lipid rafts: from model membranes to cells. Annu. Rev. Biophys. Biomol. Struct. 32, 257–283 (2003).
Sharma, P. et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589 (2004).
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).
Tian, T. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nature Cell Biol. 9, 905–914 (2007).
Plowman, S. J., Muncke, C., Parton, R. G. & Hancock, J. F. H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc. Natl Acad. Sci. USA 102, 15500–15505 (2005).
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).
Belanis, L., Plowman, S. J., Rotblat, B., Hancock, J. F. & Kloog, Y. Galectin-1 is a novel structural component and a major regulator of h-ras nanoclusters. Mol. Biol. Cell 19, 1404–1414 (2008).
Elad-Sfadia, G., Haklai, R., Ballan, E., Gabius, H. J. & Kloog, Y. Galectin-1 augments Ras activation and diverts Ras signals to Raf-1 at the expense of phosphoinositide 3-kinase. J. Biol. Chem. 277, 37169–37175 (2002).
Rotblat, B. et al. Three separable domains regulate GTP-dependent association of H-ras with the plasma membrane. Mol. Cell. Biol. 24, 6799–6810 (2004).
Prior, I. A. & Hancock, J. F. Compartmentalization of Ras proteins. J. Cell Sci. 114, 1603–1608 (2001).
Jaumot, M., Yan, J., Clyde-Smith, J., Sluimer, J. & Hancock, J. F. The linker domain of the Ha-Ras hypervariable region regulates interactions with exchange factors, Raf-1 and phosphoinositide 3-kinase. J. Biol. Chem. 277, 272–278 (2002).
Roy, S. et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Mol. Cell. Biol. 25, 6722–6733 (2005).
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).
Shalom-Feuerstein, R., Cooks, T., Raz, A. & Kloog, Y. Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells. Cancer Res. 65, 7292–7300 (2005).
Plowman, S. J., Ariotti, N., Goodall, A., Parton, R. G. & Hancock, J. F. Electrostatic interactions positively regulate K-Ras nanocluster formation and function. Mol. Cell. Biol. 28, 4377–4385 (2008).
Vetter, I. R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299–1304 (2001).
Gorfe, A. A., Babakhani, A. & McCammon, J. A. Free energy profile of H-ras membrane anchor upon membrane insertion. Angew. Chem. Int. Ed. Engl. 46, 8234–8237 (2007). Describes computational modelling of insertion of the lipids that modify HRAS into a membrane.
Gorfe, A. A., Hanzal-Bayer, M., Abankwa, D., Hancock, J. F. & McCammon, J. A. Structure and dynamics of the full-length lipid-modified H-Ras protein in a 1,2-dimyristoylglycero-3-phosphocholine bilayer. J. Med. Chem. 50, 674–684 (2007).
Thapar, R., Williams, J. G. & Campbell, S. L. NMR characterization of full-length farnesylated and non-farnesylated H-Ras and its implications for Raf activation. J. Mol. Biol. 343, 1391–1408 (2004).
Abankwa, D. et al. A novel switch region regulates H-ras membrane orientation and signal output. EMBO J. 27, 727–735 (2008).
Abankwa, D., Gorfe, A. A., Inder, K. & Hancock, J. F. Ras membrane orientation and nanodomain localization generate isoform diversity. Proc. Natl Acad. Sci. USA 107, 1130–1135 (2010).
Willumsen, B. M., Cox, A. D., Solski, P. A., Der, C. J. & Buss, J. E. Novel determinants of H-Ras plasma membrane localization and transformation. Oncogene 13, 1901–1909 (1996).
Philips, M. R. & Cox, A. D. Geranylgeranyltransferase I as a target for anti-cancer drugs. J. Clin. Invest. 117, 1223–1225 (2007).
Winter-Vann, A. M. & Casey, P. J. Post-prenylation-processing enzymes as new targets in oncogenesis. Nature Rev. Cancer 5, 405–412 (2005).
Basso, A. D., Kirschmeier, P. & Bishop, W. R. Thematic review series: lipid posttranslational modifications. Farnesyl transferase inhibitors. J. Lipid Res. 47, 15–31 (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). Shows that, in the presence of an FTI, oncogenic RAS could be alternatively prenylated by GGTase I.
Kazi, A. et al. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol. Cell. Biol. 29, 2254–2263 (2009).
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).
Schlitzer, M., Winter-Vann, A. & Casey, P. J. Non-peptidic, non-prenylic inhibitors of the prenyl protein-specific protease Rce1. Bioorg. Med. Chem. Lett. 11, 425–427 (2001).
Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004). Shows that modification of KRAS by ICMT is required for its transforming activity.
Wahlstrom, A. M. et al. Rce1 deficiency accelerates the development of K-RAS-induced myeloproliferative disease. Blood 109, 763–768 (2007).
The authors declare no competing financial interests.
Proteome-Wide PTM Statistics Curator
- Costello syndrome
A rare genetic disorder, similar to Noonan syndrome and cardio-facial-cutaneous syndrome, that is caused by an activating mutation in the gene encoding HRAS.
- Noonan syndrome
An autosomal-dominant congenital disease that results in various developmental defects, including, but not limited to, dwarfism, pulmonary valve stenosis and learning disabilities. More than half of the cases are caused by mutations in the gene encoding SHP2 and the others include gain-of-function mutations in the genes for KRAS or Son of sevenless homologue 1, placing Noonan syndrome in the RASopathy category.
- Cardio-facio-cutaneous syndrome
A rare genetic disorder that is characterized by a distinctive facial appearance, congenital cardiac malformations and learning difficulties. Like Noonan syndrome, it is a RASopathy caused by gain-of-function mutations, but in this case in the genes encoding KRAS, BRAF or MAPK/ERK kinase (MEK).
The modification of a Cys side chain sulphhydryl group with a nitrosyl group derived from nitric oxide.
- G domain
The first 169 amino acids of RAS proteins, which fold into a globular, hydrophilic protein that contains a guanine-nucleotide (G)-binding site.
- Heterotrimeric G proteins
Members of the large subfamily of guanine-nucleotide-binding proteins that signal downstream of receptors that span the plasma membrane seven times. Composed of three subunits designated α, β and γ, of which the α-subunit binds nucleotide.
- SH2 domain
(SRC homology 2 domain). One of several types of domain found in numerous signalling molecules that bind to phosphotyrosine in the context of adjacent amino acids.
- Cis–trans isomerization
Transformation, usually by an enzyme, of a peptide bond, or more commonly a peptidyl-prolyl bond, from a cis to a trans conformation or vice versa.
- Myristoyl–electrostatic switch
A term used to describe the mechanism whereby the membrane association of N-myristoylated proteins, such as myristoylated Ala-rich C-kinase substrate (MARCKS), is modulated by phosphorylation of Ser residues in an adjacent polybasic region.
- Polytopic membrane proteins
Transmembrane proteins that span cellular membranes multiple times.
- Early endosomes
Dynamic tubulovesicular organelles that form from the uncoating and fusing of clathrin-coated vesicles and represent the earliest element of the endocytic cycle.
- Late endosomes
Non-tubular organelles that mature from early endosomes, are partially acidified and fuse with primary lysosomes.
- Multivesicular bodies
Late endosomes into which vesicles have budded off to form a cluster of smaller vesicles within the larger endosome.
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Ahearn, I., Haigis, K., Bar-Sagi, D. et al. Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol 13, 39–51 (2012). https://doi.org/10.1038/nrm3255
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