Ras, an actor on many Stages: Posttranslational modifications, Localization, and Site-Specified Events

Genes and Cancer

Volumn 2, Issue 3, 2011, Pages 182-194

  Arozarena, Imanol ^a,b   Calvo, Fernando ^a   Crespo, Piero ^a  

^a UNIVERSITY OF CANTABRIA   (Spain)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Acylation; GTPases; Ras; Signal compartmentalization

Indexed keywords

GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATE; H RAS PROTEIN; K RAS PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; N RAS PROTEIN; RAS PROTEIN; UNCLASSIFIED DRUG;

ACYLATION; ARTICLE; BINDING AFFINITY; CARBOXY TERMINAL SEQUENCE; CELL COMPARTMENTALIZATION; CELL MEMBRANE; CELL MEMBRANE TRANSPORT; ENZYME ACTIVATION; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME BINDING; ENZYME INACTIVATION; ENZYME LOCALIZATION; ENZYME MODIFICATION; ENZYME PHOSPHORYLATION; ENZYME REGULATION; ENZYME SPECIFICITY; ENZYME STABILITY; ENZYME SUBSTRATE; HUMAN; INTRACELLULAR TRANSPORT; MEMBRANE BINDING; NONHUMAN; PALMITOYLATION; PRIORITY JOURNAL; PROTEIN CARBOHYDRATE INTERACTION; PROTEIN DOMAIN; PROTEIN FOLDING; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN TRANSPORT; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; UBIQUITINATION;

EID: 79960036815     PISSN: 19476019     EISSN: 19476027     Source Type: Journal    
DOI: 10.1177/1947601911409213     Document Type: Article

References (157)

1. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-65.
2. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9(7): 517-31.
3. Fotiadou PP, Takahashi C, Rajabi HN, Ewen ME. Wild-type NRas and KRas perform distinct functions during transformation. Mol Cell Biol. 2007;27(19):6742-55.
4. Haigis KM, Kendall KR, Wang Y, et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 2008;40(5):600-8.
5. Quinlan MP, Quatela SE, Philips MR, Settleman J. Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion. Mol Cell Biol. 2008;28(8):2659-74.
6. Jones MK, Jackson JH. Ras-GRF activates Ha- Ras but not N-Ras or K-Ras4B protein in vivo. J Biol Chem. 1998;273:1782-7.
7. Matallanas D, Arozarena I, Berciano MT, et al. Differences in the inhibitory specificities of H-Ras, K-Ras and N-Ras (N17) dominant negative mutants are related to their membrane microlocalization. J Biol Chem. 2003;278:4572-81.
8. Mizuno T, Kaibuchi K, Yamamoto T, et al. A stimulatory GDP/GTP exchange protein for smg p21 is active on the post-translationally processed form of c-Ki-ras p21 and rhoA p21. Proc Natl Acad Sci U S A. 1991;88(15):6442-6.
9. Bollag G, McCormick F. Differential regulation of Ras GAP and neurofibromatosis gene products activities. Nature. 1991;351:576-9.
10. Yan J, Roy S, Apolloni A, Lane A, Hancock JF. Ras isoforms vary in their ability to activate Raf and phosphoinositide 3-kinase. J Biol Chem. 1998;273:24052-6.
11. Voice JK, Klemke RI, Le A, Jackson JH. Four human Ras homologues differ in their abilities to activate Raf-1, induce transformation and stimulate cell motility. J Biol Chem. 1999;274:17164-70.
12. Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J Biol Chem. 2003;278(30):28045-51.
13. Walsh AM, Bar-Sagi D. Differential activation of the Rac pathway by Ha-Ras and Ki-Ras. J Biol Chem. 2001;276:15609-15.
14. 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. 1997;7(6):786-92.
15. Willingham MC, Pastan I, Shih TY, Scolnick EM. Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell. 1980;19(4):1005-14.
16. Choy E, Chiu VK, Silletti J, et al. Endomembrane trafficking of Ras: the CAAX motif targets proteins to the ER and Golgi. Cell. 1999;98:69-80.
17. Philips MR. Compartmentalized signalling of Ras. Biochem Soc Trans. 2005;33(Pt 4):657-61.
18. Pol A, Calvo M, Enrich C. Isolated endosomes from quiescent rat liver contain the signal transduction machinery: differential distribution of activated Raf-1 and Mek in the endocytic compartment. FEBS Lett. 1998;441(1):34-8.
19. Roy S, Wyse B, Hancock JF. H-Ras signaling and K-Ras signaling are differentially dependent on endocytosis. Mol Cell Biol. 2002;22:5128-40.
20. Gomez GA, Daniotti JL. H-Ras dynamically interacts with recycling endosomes in CHO-K1 cells: involvement of Rab5 and Rab11 in the trafficking of H-Ras to this pericentriolar endocytic compartment. J Biol Chem. 2005;280(41):34997-5010.
21. Lu A, Tebar F, Alvarez-Moya B, et al. A clathrindependent pathway leads to KRas signaling on late endosomes en route to lysosomes. J Cell Biol. 2009;184(6):863-79.
22. Fehrenbacher N, Bar-Sagi D, Philips M. Ras/ MAPK signaling from endomembranes. Mol Oncol. 2009;3(4):297-307.
23. Rebollo A, Perez-Sala D, Martinez AC. Bcl-2 differentially targets K-, N-, and H-Ras to mitochondria in IL-2 supplemented or deprived cells: implications in prevention of apoptosis. Oncogene. 1999;18(35):4930-9.
24. Wolfman JC, Wolfman A. Endogenous c-N-Ras provides a steady-state anti-apoptotic signal. J Biol Chem. 2000;275:19315-23.
25. Sengupta P, Baird B, Holowka D. Lipid rafts, fluid/fluid phase separation, and their relevance to plasma membrane structure and function. Semin Cell Dev Biol. 2007;18(5):583-90.
26. Kranenburg O, Verlaan I, Moolenar WH. Regulation of c-Ras function: cholesterol depletion affects caveolin association, GTP loading and signaling. Curr Biol. 2001;11:1880-4.
27. Prior IA, Harding A, Yan J, Sluimer J, Parton RG, Hancock JF. GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nat Cell Biol. 2001;3:368-75.
28. Prior IA, Muncke C, Parton RG, Hancock JF. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J Cell Biol. 2003;160(2):165-70.
29. Hancock JF, Parton RG. Ras plasma membrane signalling platforms. Biochem J. 2005;389(Pt 1):1-11.
30. 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. 2001;20(51):7486-93.
31. Belanis L, Plowman SJ, Rotblat B, Hancock JF, Kloog Y. Galectin-1 is a novel structural component and a major regulator of h-ras nanoclusters. Mol Biol Cell. 2008;19(4):1404-14.
32. Ashery U, Yizhar O, Rotblat B, et al. Spatiotemporal organization of Ras signaling: rasosomes and the galectin switch. Cell Mol Neurobiol. 2006;26(4-6):471-95.
33. Rotblat B, Niv H, Andre S, Kaltner H, Gabius HJ, Kloog Y. Galectin-1(L11A) predicted from a computed galectin-1 farnesyl-binding pocket selectively inhibits Ras-GTP. Cancer Res. 2004;64(9):3112-8.
34. Elad-Sfadia G, Haklai R, Balan E, Kloog Y. Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J Biol Chem. 2004;279(33):34922-30.
35. Plowman SJ, Muncke C, Parton RG, Hancock JF. H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc Natl Acad Sci U S A. 2005;102(43):15500-5.
36. Inder K, Harding A, Plowman SJ, Philips MR, Parton RG, Hancock JF. Activation of the MAPK module from different spatial locations generates distinct system outputs. Mol Biol Cell. 2008;19(11):4776-84.
37. Ulsh LS, Shih TY. Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs. Mol Cell Biol. 1984;4(8):1647-52.
38. Wright LP, Philips MR. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J Lipid Res. 2006;47(5):883-91.
39. Buss JE, Sefton BM. Direct identification of palmitic acid as the lipid attached to p21ras. Mol Cell Biol. 1986;6(1):116-22.
40. Hancock JF, Magee AI, Childs JE, Marshall CJ. All Ras proteins are polyisoprenylated but only some are palmytoylated. Cell. 1989;57:1167-77.
41. Clarke S, Vogel JP, Deschenes RJ, Stock J. Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases. Proc Natl Acad Sci U S A. 1988;85(13):4643-7.
42. Boyartchuk VL, Ashby MN, Rine J. Modulation of Ras and a-factor function by carboxyl-terminal proteolysis. Science. 1997;275(5307):1796-800.
43. Kim E, Ambroziak P, Otto JC, et al. Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells. J Biol Chem. 1999;274(13):8383-90.
44. Gutierrez L, Magee AI, Marshall CJ, Hancock JF. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis. Embo J. 1989;8(4):1093-8.
45. Dai Q, Choy E, Chiu V, et al. Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum. J Biol Chem. 1998;273(24):15030-4.
46. Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov. 2007;6(7):541-55.
47. Hancock JF, Paterson H, Marshall CJ. A polybasic domain or palmytoilation is required in addition to the CAAX motif to localize p21Ras to the membrane. Cell. 1990;63:133-9.
48. Lobo S, Greentree WK, Linder ME, Deschenes RJ. Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae. J Biol Chem. 2002;277(43):41268-73.
49. Swarthout JT, Lobo S, Farh L, et al. DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras. J Biol Chem. 2005;280(35):31141-8.
50. Mitchell DA, Vasudevan A, Linder ME, Deschenes RJ. Protein palmitoylation by a family of DHHC protein S-acyltransferases. J Lipid Res. 2006;47(6):1118-27.
51. Apolloni A, Prior IA, Lindsay M, Parton RG, Hancock JF. H-Ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol Cell Biol. 2000;20:2475-87.
52. Hancock JF, Cadwallader K, Marshall CJ. Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). Embo J. 1991;10(3):641-6.
53. Silvius JR, Bhagatji P, Leventis R, Terrone D. K-ras4B and prenylated proteins lacking "second signals" associate dynamically with cellular membranes. Mol Biol Cell. 2006;17(1):192-202.
54. Roy S, Plowman S, Rotblat B, et al. Individual palmitoyl residues serve distinct roles in H-ras trafficking, microlocalization, and signaling. Mol Cell Biol. 2005;25(15):6722-33.
55. Misaki R, Morimatsu M, Uemura T, et al. Palmitoylated Ras proteins traffic through recycling endosomes to the plasma membrane during exocytosis. J Cell Biol. 2010;191(1):23-9.
56. Huster D, Vogel A, Katzka C, et al. Membrane insertion of a lipidated ras peptide studied by FTIR, solid-state NMR, and neutron diffraction spectroscopy. J Am Chem Soc. 2003;125(14):4070-9.
57. Gorfe AA, Pellarin R, Caflisch A. Membrane localization and flexibility of a lipidated ras peptide studied by molecular dynamics simulations. J Am Chem Soc. 2004;126(46):15277-86.
58. Thissen JA, Gross JM, Subramanian K, Meyer T, Casey PJ. Prenylation-dependent association of Ki-Ras with microtubules: evidence for a role in subcellular trafficking. J Biol Chem. 1997;272(48):30362-70.
59. Magee AI, Gutierrez L, McKay IA, Marshall CJ, Hall A. Dynamic fatty acylation of p21N-ras. Embo J. 1987;6(11):3353-7.
60. Goodwin JS, Drake KR, Rogers C, et al. Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway. J Cell Biol. 2005;170(2):261-72.
61. Rocks O, Peyker A, Kahms M, et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science. 2005;307(5716):1746-52.
62. Camp LA, Hofmann SL. Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras. J Biol Chem. 1993;268(30):22566-74.
63. Duncan JA, Gilman AG. A cytoplasmic acylprotein thioesterase that removes palmitate from G protein alpha subunits and p21(RAS). J Biol Chem. 1998;273(25):15830-7.
64. Dekker FJ, Rocks O, Vartak N, et al. Smallmolecule inhibition of APT1 affects Ras localization and signaling. Nat Chem Biol. 2010;6(6): 449-56.
65. Elad-Sfadia G, Haklai R, Ballan E, Gabius HJ, Kloog Y. Galectin-1 augments Ras activation and diverts Ras signals to Raf-1 at the expense of phosphoinositide 3-kinase. J Biol Chem. 2002;277(40):37169-75.
66. Nancy V, Callebaut I, El Marjou A, de Gunzburg J. The delta subunit of retinal rod cGMP phosphodiesterase regulates the membrane association of Ras and Rap GTPases. J Biol Chem. 2002;277(17):15076-84.
67. Schroeder H, Leventis R, Rex S, et al. S-Acylation and plasma membrane targeting of the farnesylated carboxyl-terminal peptide of N-ras in mammalian fibroblasts. Biochemistry. 1997;36(42):13102-9.
68. Fivaz M, Meyer T. Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/calmodulin. J Cell Biol. 2005;170(3):429-41.
69. Lorentzen A, Kinkhabwala A, Rocks O, Vartak N, Bastiaens PI. Regulation of Ras localization by acylation enables a mode of intracellular signal propagation. Sci Signal. 2010;3(140):ra68.
70. Wang TY, Leventis R, Silvius JR. Partitioning of lipidated peptide sequences into liquid-ordered lipid domains in model and biological membranes. Biochemistry. 2001;40(43):13031-40.
71. Thapar R, Williams JG, Campbell SL. NMR characterization of full-length farnesylated and nonfarnesylated H-Ras and its implications for Raf activation. J Mol Biol. 2004;343(5):1391-408.
72. Baker TL, Zheng H, Walker J, Coloff JL, Buss JE. Distinct rates of palmitate turnover on membrane- bound cellular and oncogenic H-ras. J Biol Chem. 2003;278(21):19292-300.
73. Rocks O, Gerauer M, Vartak N, et al. The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins. Cell. 2010;141(3):458-71.
74. Jaumot M, Yan J, Clyde-Smith J, Sluimer J, Hancock JF. The linker domain of the Ha-Ras hypervariable region regulates interactions with exchange factors, Raf-1 and phosphoinositide 3-kinase. J Biol Chem. 2002;277:272-8.
75. Laude AJ, Prior IA. Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J Cell Sci. 2008;121(Pt 4):421-7.
76. Rotblat B, Prior IA, Muncke C, et al. Three separable domains regulate GTP-dependent association of H-ras with the plasma membrane. Mol Cell Biol. 2004;24(15):6799-810.
77. Abankwa D, Hanzal-Bayer M, Ariotti N, et al. A novel switch region regulates H-ras membrane orientation and signal output. Embo J. 2008;27(5):727-35.
78. Ballester R, Furth ME, Rosen OM. Phorbol esterand protein kinase C-mediated phosphorylation of the cellular Kirsten ras gene product. J Biol Chem. 1987;262(6):2688-95.
79. Bivona TG, Quatela SE, Bodemann BO, 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. 2006;21(4):481-93.
80. Lopez-Alcala C, Alvarez-Moya B, Villalonga P, Calvo M, Bachs O, Agell N. Identification of essential interacting elements in K-Ras/calmodulin binding and its role in K-Ras localization. J Biol Chem. 2008;283(16):10621-31.
81. Plowman SJ, Ariotti N, Goodall A, Parton RG, Hancock JF. Electrostatic interactions positively regulate K-Ras nanocluster formation and function. Mol Cell Biol. 2008;28(13): 4377-85.
82. Villalonga P, Lopez-Alcala C, Bosch M, et al. Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling. Mol Cell Biol. 2001;21(21):7345-54.
83. Villalonga P, Lopez-Alcala C, Chiloeches A, et al. Calmodulin prevents activation of Ras by PKC in 3T3 fibroblasts. J Biol Chem. 2002;277(40): 37929-35.
84. Alvarez-Moya B, Lopez-Alcala C, Drosten M, Bachs O, Agell N. K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function. Oncogene. 2010;29(44):5911-22.
85. Jura N, Scotto-Lavino E, Sobczyk A, Bar-Sagi D. Differential modification of Ras proteins by ubiquitination. Mol Cell. 2006;21(5):679-87.
86. Xu L, Lubkov V, Taylor LJ, Bar-Sagi D. Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr Biol. 2010;20(15):1372-7.
87. Burrows JF, Kelvin AA, McFarlane C, et al. USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity. J Biol Chem. 2009;284(14):9587-95.
88. de la Vega M, Burrows JF, McFarlane C, Govender U, Scott CJ, Johnston JA. The deubiquitinating enzyme USP17 blocks N-Ras membrane trafficking and activation but leaves K-Ras unaffected. J Biol Chem. 2010;285(16):12028-36.
89. Ghomashchi F, Zhang X, Liu L, Gelb MH. Binding of prenylated and polybasic peptides to membranes: affinities and intervesicle exchange. Biochemistry. 1995;34(37):11910-8.
90. Leventis R, Silvius JR. Lipid-binding characteristics of the polybasic carboxy-terminal sequence of K-ras4B. Biochemistry. 1998;37(20):7640-8.
91. Gomez GA, Daniotti JL. Electrical properties of plasma membrane modulate subcellular distribution of K-Ras. FEBS J. 2007;274(9):2210-28.
92. Eisenberg S, Shvartsman DE, Ehrlich M, Henis YI. Clustering of raft-associated proteins in the external membrane leaflet modulates internal leaflet H-ras diffusion and signaling. Mol Cell Biol. 2006;26(19):7190-200.
93. Goodwin JS, Drake KR, Remmert CL, Kenworthy AK. Ras diffusion is sensitive to plasma membrane viscosity. Biophys J. 2005;89(2):1398-410.
94. Niv H, Gutman O, Kloog Y, Henis YI. Activated K-Ras and H-Ras display different interactions with saturable non-raft sites at the surface of live cells. J Cell Biol. 2002;157:865-72.
95. Roy S, Luetterforst R, Harding A, et al. Dominantnegative caveolin inhibits H-ras function by disrupting cholesterol-rich plasma membrane domains. Nat Cell Biol. 1999;1:98-105.
96. Quilliam LA, Khosravi-Far R, Huff SY, Der CJ. Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays. 1995;17(5):395-404.
97. Caloca MJ, Zugaza JL, Bustelo XR. Exchange factors of the RasGRP family mediate Ras activation in the Golgi. J Biol Chem. 2003;278:33465-73.
98. Bivona TG, Perez de Castro I, Ahearn IM, et al. Phospholipase Cg activates Ras on the Golgi apparatus by means of RasGRP1. Nature. 2003;424:694-8.
99. Mor A, Campi G, Du G, et al. The lymphocyte function-associated antigen-1 receptor costimulates plasma membrane Ras via phospholipase D2. Nat Cell Biol. 2007;9(6):713-9.
100. Arozarena I, Matallanas D, Berciano MT, et al. Activation of H-Ras in the endoplasmic reticulum by the RasGRF family guanine nucleotide exchange factors. Mol Cell Biol. 2004;24(4):1516-30.
101. Clyde-Smith J, Silins G, Gartside M, et al. Characterization of RasGRP2, a plasma membranetargeted, dual specificity Ras/Rap exchange factor. J Biol Chem. 2000;275(41):32260-7.
102. Omerovic J, Laude AJ, Prior IA. Ras proteins: paradigms for compartmentalised and isoform-specific signalling. Cell Mol Life Sci. 2007;64(19-20):2575-89.
103. Shalom-Feuerstein R, Levy R, Makovski V, Raz A, Kloog Y. Galectin-3 regulates RasGRP4- mediated activation of N-Ras and H-Ras. Biochim Biophys Acta. 2008;1783(6):985-93.
104. Ibiza S, Perez-Rodriguez A, Ortega A, et al. Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells. Proc Natl Acad Sci U S A. 2008;105(30):10507-12.
105. Mochizuki N, Yamashita S, Kurokawa K, et al. Spatio-temporal images of growth factor induced activation of Ras and Rap1. Nature. 2001;411:1065-8.
106. Ohba Y, Kurokawa K, Matsuda M. Mechanism of the spatio-temporal regulation of Ras and Rap1. Embo J. 2003;22(4):859-69.
107. Augsten M, Pusch R, Biskup C, et al. Live-cell imaging of endogenous Ras-GTP illustrates predominant Ras activation at the plasma membrane. EMBO Rep. 2006;7(1):46-51.
108. Nakamura R, Furuno T, Nakanishi M. The plasma membrane shuttling of CAPRI is related to regulation of mast cell activation. Biochem Biophys Res Commun. 2006;347(1):363-8.
109. Cozier GE, Lockyer PJ, Reynolds JS, et al. GAP1IP4BP contains a novel group I pleckstrin homology domain that directs constitutive plasma membrane association. J Biol Chem. 2000;275(36):28261-8.
110. Li C, Cheng Y, Gutmann DA, Mangoura D. Differential localization of the neurofibromatosis 1 (NF1) gene product, neurofibromin, with the F-actin or microtubule cytoskeleton during differentiation of telencephalic neurons. Brain Res Dev Brain Res. 2001;130(2):231-48.
111. Nordlund M, Gu X, Shipley MT, Ratner N. Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons. J Neurosci. 1993;13(4):1588-600.
112. Grewal T, Enrich C. Molecular mechanisms involved in Ras inactivation: the annexin A6- p120GAP complex. Bioessays. 2006;28(12): 1211-20.
113. Chiu VK, Bivona T, Hach A, et al. Ras signaling on the endoplasmic reticulum and the Golgi. Nat Cell Biol. 2002;4:343-50.
114. Taub N, Teis D, Ebner HL, Hess MW, Huber LA. Late endosomal traffic of the epidermal growth factor receptor ensures spatial and temporal fidelity of mitogen-activated protein kinase signaling. Mol Biol Cell. 2007;18(12):4698-710.
115. Abankwa D, Gorfe AA, Inder K, Hancock JF. Ras membrane orientation and nanodomain localization generate isoform diversity. Proc Natl Acad Sci U S A. 2010;107(3):1130-5.
116. Tian T, Harding A, Inder K, Plowman S, Parton RG, Hancock JF. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat Cell Biol. 2007;9(8):905-14.
117. Eungdamrong NJ, Iyengar R. Compartmentspecific feedback loop and regulated trafficking can result in sustained activation of Ras at the Golgi. Biophys J. 2007;92(3):808-15.
118. Harding A, Tian T, Westbury E, Frische E, Hancock JF. Subcellular localization determines MAP kinase signal output. Curr Biol. 2005;15(9):869-73.
119. Morice C, Nothias F, Konig S, et al. Raf-1 and B-Raf proteins have similar regional distributions but differential subcellular localization in adult rat brain. Eur J Neurosci. 1999; 11(6):1995-2006.
120. Yuryev A, Ono M, Goff SA, Macaluso F, Wennogle LP. Isoform-specific localization of A-RAF in mitochondria. Mol Cell Biol. 2000;20(13):4870-8.
121. Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature. 2004;427(6971):256-60.
122. Mitin NY, Ramocki MB, Zullo AJ, Der CJ, Konieczny SF, Taparowsky EJ. Identification and characterization of rain, a novel Ras-interacting protein with a unique subcellular localization. J Biol Chem. 2004;279(21):22353-61.
123. Hekman M, Hamm H, Villar AV, et al. Associations of B- and C-Raf with cholesterol, phosphatidylserine, and lipid second messengers: preferential binding of Raf to artificial lipid rafts. J Biol Chem. 2002;277(27):24090-102.
124. Klysik J, Theroux SJ, Sedivy JM, Moffit JS, Boekelheide K. Signaling crossroads: the function of Raf kinase inhibitory protein in cancer, the central nervous system and reproduction. Cell Signal. 2008;20(1):1-9.
125. Matallanas D, Sanz-Moreno V, Arozarena I, 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. 2006;26(1):100-16.
126. Casar B, Arozarena I, Sanz-Moreno V, et al. Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol Cell Biol. 2009;29(5):1338-53.
127. Kholodenko BN, Hancock JF, Kolch W. Signalling ballet in space and time. Nat Rev Mol Cell Biol. 2010;11(6):414-26.
128. Yao Z, Seger R. The ERK signaling cascade: views from different subcellular compartments. Biofactors. 2009;35(5):407-16.
129. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6(11):827-37.
130. Dhanasekaran DN, Kashef K, Lee CM, Xu H, Reddy EP. Scaffold proteins of MAP-kinase modules. Oncogene. 2007;26(22):3185-202.
131. Teis D, Wunderlich W, Huber LA. Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev Cell. 2002;3(6):803-14.
132. Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell. 2004;7(1):33-44.
133. Ishibe S, Joly D, Zhu X, Cantley LG. Phosphorylation- dependent paxillin-ERK association mediates hepatocyte growth factorstimulated epithelial morphogenesis. Mol Cell. 2003;12(5):1275-85.
134. Shenoy SK, Lefkowitz RJ. Receptorspecific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. J Biol Chem. 2005;280(15):15315-24.
135. DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW. Betaarrestin- dependent endocytosis of proteinaseactivated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol. 2000;148(6):1267-81.
136. Xiong S, Zhao Q, Rong Z, et al. hSef inhibits PC-12 cell differentiation by interfering with Rasmitogen- activated protein kinase MAPK signaling. J Biol Chem. 2003;278(50):50273-82.
137. Casar B, Pinto A, Crespo P. Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes. Mol Cell. 2008;31(5):708-21.
138. Yan H, Chin ML, Horvath EA, Kane EA, Pfleger CM. Impairment of ubiquitylation by mutation in Drosophila E1 promotes both cellautonomous and non-cell-autonomous Ras- ERK activation in vivo. J Cell Sci. 2009;122 (Pt 9):1461-70.
139. Jiang X, Sorkin A. Coordinated traffic of Grb2 and Ras during epidermal growth factor receptor endocytosis visualized in living cells. Mol Biol Cell. 2002;13(5):1522-35.
140. Howe CL, Valletta JS, Rusnak AS, Mobley WC. NGF signaling from clathrin-coated vesicles: evidence that signaling endosomes serve as a platform for the Ras-MAPK pathway. Neuron. 2001;32(5):801-14.
141. Kranenburg O, Verlaan I, Moolenaar WH. Dynamin is required for the activation of mitogen-activated protein (MAP) kinase by MAP kinase kinase. J Biol Chem. 1999;274(50):35301-4.
142. Esteban LM, Vicario-Arbejon C, Fernandez- Salguero P, et al. Targeted genomic disruption of H-ras and N-ras individuallly or in combination, reveals the dispensability of both loci for mouse growth and development. Mol Cel Biol. 2001;21:1444-52.
143. Agudo-Ibanez L, Nunez F, Calvo F, Berenjeno IM, Bustelo XR, Crespo P. Transcriptomal profiling of site-specific Ras signals. Cell Signal. 2007;19(11):2264-76.
144. Onken B, Wiener H, Philips MR, Chang EC. Compartmentalized signaling of Ras in fission yeast. Proc Natl Acad Sci U S A. 2006;103(24):9045-50.
145. Traverse S, Seedorf K, Paterson H, Marshall CJ, Cohen P, Ullrich A. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol. 1994;4(8):694-701.
146. Hart KC, Donoghue DJ. Derivatives of activated H-ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location. Oncogene. 1997;14(8):945-53.
147. Feng L, Xie X, Ding Q, et al. Spatial regulation of Raf kinase signaling by RKTG. Proc Natl Acad Sci U S A. 2007;104(36):14348-53.
148. Beranger F, Goud B, Tavitian A, de Gunzburg J. Association of the Ras-antagonistic Rap1/ Krev-1 proteins with the Golgi complex. Proc Natl Acad Sci U S A. 1991;88(5):1606-10.
149. Daniels MA, Teixeiro E, Gill J, et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature. 2006;444(7120):724-9.
150. Perez de Castro I, Bivona TG, Philips MR, Pellicer A. Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Mol Cell Biol. 2004;24(8):3485-96.
151. Wolfman JC, Palmby T, Der CJ, Wolfman A. Cellular N-Ras promotes cell survival by downregulation of Jun N-terminal protein kinase and p38. Mol Cell Biol. 2002;22(5):1589-606.
152. Wolfman JC, Planchon SM, Liao J, Wolfman A. Structural and functional consequences of c-N-Ras constitutively associated with intact mitochondria. Biochim Biophys Acta. 2006;1763(10):1108-24.
153. Denoyelle C, Abou-Rjaily G, Bezrookove V, et al. Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway. Nat Cell Biol. 2006;8(10):1053-63.
154. Babia T, Ayala I, Valderrama F, et al. N-Ras induces alterations in Golgi complex architecture and in constitutive protein transport. J Cell Sci. 1999;112(Pt 4):477-89.
155. Mansilla F, Birkenkamp-Demtroder K, Kruhoffer M, et al. Differential expression of DHHC9 in microsatellite stable and instable human colorectal cancer subgroups. Br J Cancer. 2007;96(12):1896-903.
156. Calvo F, Agudo-Ibanez L, Crespo P. The Ras- ERK pathway: understanding site-specific signaling provides hope of new anti-tumor therapies. Bioessays. 2010;32(5):412-21.
157. Matallanas D, Crespo P. New druggable targets in the Ras pathway? Curr Opin Mol Ther. 2010;12(6):674-83.