Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation

Expert Review of Proteomics

Volumn 12, Issue 6, 2015, Pages 669-682

  Nussinov, Ruth ^a,b   Tsai, Chung Jung ^a   Muratcioglu, Serena ^c   Jang, Hyunbum ^a   Gursoy, Attila ^c   Keskin, Ozlem ^c  

^a FREDERICK NATIONAL LABORATORY FOR CANCER RESEARCH   (United States)

^b TEL AVIV UNIVERSITY   (Israel)

^c KOÇ UNIVERSITY   (Turkey)

Author keywords

calmodulin; cell cycle; K Ras; K Ras4B; KRAS4B; lung cancer; pancreatic cancer; PI3K; Raf; RalGDS; Ras effectors; Ras isoforms

Indexed keywords

CALMODULIN; CYCLIN D1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR 1B; CYCLIN E; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INITIATION FACTOR 4E; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; PHOSPHATIDYLETHANOLAMINE BINDING PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE B; PROTEIN P110; PROTEIN P16; PROTEIN P21; RAF PROTEIN; RAS ASSOCIATION DOMAIN FAMILY PROTEIN 1A; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR E2F; TRANSCRIPTION FACTOR FKHRL1; TRANSCRIPTION FACTOR FOXO; GUANINE NUCLEOTIDE EXCHANGE FACTOR; KRAS PROTEIN, HUMAN;

ACTIN FILAMENT; ALLOSTERISM; AMINO TERMINAL SEQUENCE; CARBOXY TERMINAL SEQUENCE; CARCINOGENESIS; CELL AGING; CELL CYCLE G1 PHASE; CELL CYCLE REGULATION; CELL CYCLE S PHASE; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; CONFORMATIONAL TRANSITION; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; GENE OVEREXPRESSION; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MITOSIS; NONHUMAN; POINT MUTATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION; ANIMAL; G1 PHASE CELL CYCLE CHECKPOINT; METABOLISM;

ANIMALS; CARCINOGENESIS; G1 PHASE CELL CYCLE CHECKPOINTS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS P21(RAS); RAF KINASES; RAL GUANINE NUCLEOTIDE EXCHANGE FACTOR; SIGNAL TRANSDUCTION;

EID: 84947494280     PISSN: 14789450     EISSN: 17448387     Source Type: Journal    
DOI: 10.1586/14789450.2015.1100079     Document Type: Review

References (165)

1. Ahearn IM, Haigis K, Bar-Sagi D, et al. Regulating the regulator: post-translational modification of RAS. Nat Rev Mol Cell Biol. 2012; 13 (1): 39-51.
2. Rusanescu G, Gotoh T, Tian X, et al. Regulation of Ras signaling specificity by protein kinase C. Mol Cell Biol. 2001; 21 (8): 2650-2658.
3. Moodie SA, Willumsen BM, Weber MJ, et al. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science. 1993; 260 (5114): 1658-1661.
4. Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993; 74 (1): 205-214.
5. Warne PH, Viciana PR, Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993; 364 (6435): 352-355.
6. Zhang XF, Settleman J, Kyriakis JM, et al. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993; 364 (6435): 308-313.
7. Castellano E, Downward J. RAS interaction with PI3K: more than just another effector pathway. Gene Canc. 2011; 2 (3): 261-274.
8. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002; 2 (7): 489-501.
9. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11 (11): 761-774.
10. Eser S, Schnieke A, Schneider G, et al. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014; 111 (5): 817-822.
11. Goi T, Rusanescu G, Urano T, et al. Ral-specific guanine nucleotide exchange factor activity opposes other Ras effectors in PC12 cells by inhibiting neurite outgrowth. Mol Cell Biol. 1999; 19 (3): 1731-1741.
12. Linnemann T, Kiel C, Herter P, et al. The activation of RalGDS can be achieved independently of its Ras binding domain. Implications of an activation mechanism in Ras effector specificity and signal distribution. J Biol Chem. 2002; 277 (10): 7831-7837.
13. Herrmann C, Horn G, Spaargaren M, et al. Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. J Biol Chem. 1996; 271 (12): 6794-6800.
14. Gentry LR, Martin TD, Reiner DJ, et al. Ral small GTPase signaling and oncogenesis: more than just 15minutes of fame. Biochim Biophys Acta. 2014; 1843 (12): 2976-2988.
15. Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012; 72 (10): 2457-2467.
16. Housden BE, Perrimon N. Spatial and temporal organization of signaling pathways. Trends Biochem Sci. 2014; 39 (10): 457-464.
17. Vandal G, Geiling B, Dankort D. Ras effector mutant expression suggest a negative regulator inhibits lung tumor formation. PloS one. 2014; 9 (1): e84745.
18. Nussinov R, Muratcioglu S, Tsai CJ, et al. The key role of calmodulin in KRAS -driven adenocarcinomas. Mol Cancer Res. 2015;13(9):1265-1273.
19. Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003; 3 (1): 11-22.
20. Shields JM, Pruitt K, McFall A, et al. Understanding Ras: it aint over til its over. Trends Cell Biol. 2000; 10 (4): 147-154.
21. Muratcioglu S, Chavan TS, Freed BC, et al. GTP-dependent K-Ras dimerization. Structure. 2015; 23: 1325-1335.
22. Nan X, Tamguney TM, Collisson EA, et al. Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway. Proc Natl Acad Sci U S A. 2015; 112 (26): 7996-8001.
23. Woods D, Parry D, Cherwinski H, et al. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 1997; 17 (9): 5598-5611.
24. Zhu J, Woods D, McMahon M, et al. Senescence of human fibroblasts induced by oncogenic Raf. Gene Dev. 1998; 12 (19): 2997-3007.
25. Lin AW, Barradas M, Stone JC, et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Gene Dev. 1998; 12 (19): 3008-3019.
26. Serrano M, Lin AW, McCurrach ME, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88 (5): 593-602.
27. Xu Y, Li N, Xiang R, et al. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem Sci. 2014; 39 (6): 268-276.
28. Wang W, Chen JX, Liao R, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002; 22 (10): 3389-3403.
29. Urosevic J, Garcia-Albeniz X, Planet E, et al. Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat Cell Biol. 2014; 16 (7): 685-694.
30. Neel NF, Martin TD, Stratford JK, et al. The RalGEF-Ral effector signaling network: the road less traveled for anti-Ras drug discovery. Gene Canc. 2011; 2 (3): 275-287.
31. Jang H, Abraham SJ, Chavan TS, et al. Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region. J Biol Chem. 2015; 290 (15): 9465-9477.
32. Tsygankova OM, Wang H, Meinkoth JL. Tumor cell migration and invasion are enhanced by depletion of Rap1 GTPase-activating protein (Rap1GAP). J Biol Chem. 2013; 288 (34): 24636-24646.
33. Dong X, Tang W, Stopenski S, et al. RAP1GAP inhibits cytoskeletal remodeling and motility in thyroid cancer cells. Endocr Relat Cancer. 2012; 19 (4): 575-588.
34. Qiu T, Qi X, Cen J, et al. Rap1GAP alters leukemia cell differentiation, apoptosis and invasion in vitro. Oncol Rep. 2012; 28 (2): 622-628.
35. Djos A, Martinsson T, Kogner P, et al. The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma. Mol Cancer. 2012; 11: 40.
36. Fernandes MS, Carneiro F, Oliveira C, et al. Colorectal cancer and RASSF family-a special emphasis on RASSF1A. Int J Cancer. 2013; 132 (2): 251-258.
37. Kuo KK, Kuo CJ, Chiu CY, et al. Quantitative proteomic analysis of differentially expressed protein profiles involved in pancreatic ductal adenocarcinoma. Pancreas. 2015. DOI: 10.1097/MPA.0000000000000388.
38. Baron B, Fujioka T, Kitagawa T, et al. Comparative proteomic analysis of two stress-management strategies in pancreatic cancer. Cancer Genomics Proteomics. 2015; 12 (2): 83-87.
39. Dong Q, Zhang Y, Yang XH, et al. Serum calcium level used as a prognostic predictor in patients with resectable pancreatic ductal adenocarcinoma. Clin Res Hepatol Gastroenterol. 2014; 38 (5): 639-648.
40. Bauer I, Grozio A, Lasiglie D, et al. The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. J Biol Chem. 2012; 287 (49): 40924-40937.
41. Genkinger JM, Wang M, Li R, et al. Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Ann Oncol. 2014; 25 (6): 1106-1115.
42. Choi DL, Jang SJ, Cho S, et al. Inhibition of cellular proliferation and induction of apoptosis in human lung adenocarcinoma A549 cells by T-type calcium channel antagonist. Bioorg Med Chem Lett. 2014; 24 (6): 1565-1570.
43. Ay AS, Benzerdjeb N, Sevestre H, et al. Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation. PloS one. 2013; 8 (9): e72889.
44. Chung L, Phillips L, Lin MZ, et al. A novel truncated form of S100P predicts disease-free survival in patients with lymph node positive breast cancer. Cancer Lett. 2015;368(1):64-70.
45. Schaal C, Padmanabhan J, Chellappan S. The role of nAChR and calcium signaling in pancreatic cancer initiation and progression. Cancers (Basel). 2015; 7 (3): 1447-1471.
46. Liu G, Shi Z, Jiao S, et al. Structure of MST2 SARAH domain provides insights into its interaction with RAPL. J Struct Biol. 2014; 185 (3): 366-374.
47. Hwang E, Cheong HK, Ul Mushtaq A, et al Structural basis of the heterodimerization of the MST and RASSF SARAH domains in the Hippo signalling pathway. Acta Crystallogr D Biol Crystallogr. 2014; 70 (Pt 7): 1944-1953.
48. Takahashi M, Dillon TJ, Liu C, et al. Protein kinase A-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. J Biol Chem. 2013; 288 (39): 27712-27723.
49. 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): 7345-7354.
50. Vos MD, Martinez A, Ellis CA, et al. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J Biol Chem. 2003; 278 (24): 21938-21943.
51. Vos MD, Ellis CA, Elam C, et al. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J Biol Chem. 2003; 278 (30): 28045-28051.
52. Elad-Sfadia G, Haklai R, Balan E, et al. 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): 34922-34930.
53. Bhagatji P, Leventis R, Rich R, et al. Multiple cellular proteins modulate the dynamics of K-ras association with the plasma membrane. Biophys J. 2010; 99 (10): 3327-3335.
54. Ho A, Dowdy SF. Regulation of G(1) cell-cycle progression by oncogenes and tumor suppressor genes. Curr Opin Genet Dev. 2002; 12 (1): 47-52.
55. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9 (3): 153-166.
56. Aleem E, Arceci RJ. Targeting cell cycle regulators in hematologic malignancies. Frontiers Cell Developmental Biology. 2015; 3: 16-16.
57. Massague J. G1 cell-cycle control and cancer. Nature. 2004; 432 (7015): 298-306.
58. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Biol. 2008; 9 (7): 517-531.
59. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle (Georgetown, Tex.). 2003; 2 (4): 339-345.
60. Aktas H, Cai H, Cooper GM. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27(KIP1). Mol Cell Biol. 1997; 17 (7): 3850-3857.
61. Drosten M, Dhawahir A, Sum EYM, et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J. 2010; 29 (6): 1091-1104.
62. Coleman ML, Marshall CJ, Olson MF. RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Biol. 2004; 5 (5): 355-366.
63. Bertoli C, Skotheim JM, de Bruin RAM. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Biol. 2013; 14 (8): 518-528.
64. Dyson N. The regulation of E2F by pRB-family proteins. Gene Dev. 1998; 12 (15): 2245-2262.
65. Yao G, Lee TJ, Mori S, et al. A bistable Rb-E2F switch underlies the restriction point. Nat Cell Biol. 2008; 10 (4): 476-U255.
66. Weinberg RA. The retinoblastoma protein and cell-cycle control. Cell. 1995; 81 (3): 323-330.
67. Sherr CJ, Roberts JM. Inhibitors of mammalian G(1) cyclin-dependent kinases. Gene Dev. 1995; 9 (10): 1149-1163.
68. Hitomi M, Yang K, Guo Y, et al. p27Kip1 and cyclin dependent kinase 2 regulate passage through the restriction point. Cell Cycle. 2006; 5 (19): 2281-2289.
69. Moeller SJ, Sheaff RJ. G1 phase: components, conundrums, context. In: Kaldis P, editor. Results Probl Cell Differ. 2006;42:1-29.
70. Jones SM, Kazlauskas A. Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat Cell Biol. 2001; 3 (2): 165-172.
71. Foster DA, Yellen P, Xu L, et al. Regulation of G1 cell cycle progression: distinguishing the restriction point from a nutrient-sensing cell growth checkpoint(s). Gene Canc. 2010; 1 (11): 1124-1131.
72. Blagosklonny MV, Pardee AB. The restriction point of the cell cycle. Cell Cycle (Georgetown, Tex.). 2002; 1 (2): 103-110.
73. Smith EJ, Leone G, DeGregori J, et al. The accumulation of an E2F-p130 transcriptional repressor distinguishes a G(0) cell state from a G(1) cell state. Mol Cell Biol. 1996; 16 (12): 6965-6976.
74. Campisi J, di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Biol. 2007; 8 (9): 729-740.
75. Buttitta LA, Edgar BA. Mechanisms controlling cell cycle exit upon terminal differentiation. Curr Opin Cell Biol. 2007; 19 (6): 697-704.
76. Demidenko ZN, Blagosklonny MV. Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008; 7 (21): 3355-3361.
77. Kyriakis JM. Thinking outside the box about Ras. J Biol Chem. 2009; 284 (17): 10993-10994.
78. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol. 2004; 5 (11): 875-885.
79. Rozengurt E. Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol. 2007; 213 (3): 589-602.
80. McKay MM, Morrison DK. Integrating signals from RTKs to ERK/MAPK. Oncogene. 2007; 26 (22): 3113-3121.
81. Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011; 36 (6): 320-328.
82. Anjum R, Blenis J. The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol. 2008; 9 (10): 747-758.
83. Dhillon AS, Hagan S, Rath O, et al. MAP kinase signalling pathways in cancer. Oncogene. 2007; 26 (22): 3279-3290.
84. Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells Devoted Mol Cell Mech. 2003; 8 (2): 131-144.
85. Bartkova J, Rezaei N, Liontos M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006; 444 (7119): 633-637.
86. Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444 (7119): 638-642.
87. Wang X, McGowan CH, Zhao M, et al. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000; 20 (13): 4543-4552.
88. Suram A, Kaplunov J, Patel PL, et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 2012; 31 (13): 2839-2851.
89. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010; 40 (2): 310-322.
90. Sun P. Contact inhibition against senescence. Oncotarget. 2014; 5 (17): 7212-7213.
91. Leontieva OV, Demidenko ZN, Blagosklonny MV. Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Proc Natl Acad Sci U S A. 2014; 111 (24): 8832-8837.
92. Lim KH, O'Hayer K, Adam SJ, et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol. 2006; 16 (24): 2385-2394.
93. Rondaij MG, Bierings R, van Agtmaal EL, et al Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells. Blood. 2008; 112 (1): 56-63.
94. Bhattacharya M, Anborgh PH, Babwah AV, et al. Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nat Cell Biol. 2002; 4 (8): 547-555.
95. White MA, Vale T, Camonis JH, et al. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J Biol Chem. 1996; 271 (28): 16439-16442.
96. Hannah MJ, Skehel P, Erent M, et al. Differential kinetics of cell surface loss of von Willebrand factor and its propolypeptide after secretion from Weibel-Palade bodies in living human endothelial cells. J Biol Chem. 2005; 280 (24): 22827-22830.
97. Herrmann C, Martin GA, Wittinghofer A. Quantitative analysis of the complex between p21ras and the Ras-binding domain of the human Raf-1 protein kinase. J Biol Chem. 1995; 270 (7): 2901-2905.
98. Geyer M, Herrmann C, Wohlgemuth S, et al. Structure of the Ras-binding domain of RalGEF and implications for Ras binding and signalling. Nat Struct Biol. 1997; 4 (9): 694-699.
99. D'Adamo DR, Novick S, Kahn JM, et al. rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral. Oncogene. 1997; 14 (11): 1295-1305.
100. Hernandez-Munoz I, Malumbres M, Leonardi P, et al. The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways. Oncogene. 2000; 19 (23): 2745-2757.
101. Hao Y, Wong R, Feig LA. RalGDS couples growth factor signaling to Akt activation. Mol Cell Biol. 2008; 28 (9): 2851-2859.
102. Gloerich M, Bos JL. Regulating Rap small G-proteins in time and space. Trends Cell Biol. 2011; 21 (10): 615-623.
103. Albright CF, Giddings BW, Liu J, et al. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J. 1993; 12 (1): 339-347.
104. Matsubara K, Kishida S, Matsuura Y, et al. Plasma membrane recruitment of RalGDS is critical for Ras-dependent Ral activation. Oncogene. 1999; 18 (6): 1303-1312.
105. Beranger F, Goud B, Tavitian A, et al. Association of the Ras-antagonistic Rap1/Krev-1 proteins with the Golgi complex. Proc Natl Acad Sci U S A. 1991; 88 (5): 1606-1610.
106. Pizon V, Desjardins M, Bucci C, et al. Association of Rap1a and Rap1b proteins with late endocytic/phagocytic compartments and Rap2a with the Golgi complex. J Cell Sci. 1994; 107 (Pt 6): 1661-1670.
107. Maridonneau-Parini I, de Gunzburg J. Association of rap1 and rap2 proteins with the specific granules of human neutrophils. Translocation to the plasma membrane during cell activation. J Biol Chem. 1992; 267 (9): 6396-6402.
108. Berger G, Quarck R, Tenza D, et al. Ultrastructural localization of the small GTP-binding protein Rap1 in human platelets and megakaryocytes. Br J Haematol. 1994; 88 (2): 372-382.
109. Feig LA, Urano T, Cantor S. Evidence for a Ras/Ral signaling cascade. Trends Biochem Sci. 1996; 21 (11): 438-441.
110. Janosi L, Li Z, Hancock JF, et al. Organization, dynamics, and segregation of Ras nanoclusters in membrane domains. Proc Natl Acad Sci U S A. 2012; 109 (21): 8097-8102.
111. Parker JA, Mattos C. The Ras-membrane interface: isoform-specific differences in the catalytic domain. Mol Cancer Res. 2015;13(4):595-603.
112. Mazur PK, Reynoird N, Khatri P, et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. 2014; 510 (7504): 283-287.
113. Ying H, DePinho RA. Cancer signaling: when phosphorylation meets methylation. Cell Res. 2014; 24 (11): 1282-1283.
114. Sasaki AT, Carracedo A, Locasale JW, et al. Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors. Sci Signal. 2011; 4 (163): ra13.
115. Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol. 2003; 13 (8): 419-425.
116. Corbit KC, Trakul N, Eves EM, et al. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J Biol Chem. 2003; 278 (15): 13061-13068.
117. Tsai FD, Lopes MS, Zhou M, et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc Natl Acad Sci U S A. 2015; 112 (3): 779-784.
118. Liao J, Planchon SM, Wolfman JC, et al. Growth factor-dependent AKT activation and cell migration requires the function of c-K(B)-Ras versus other cellular ras isoforms. J Biol Chem. 2006; 281 (40): 29730-29738.
119. Agell N, Bachs O, Rocamora N, et al. Modulation of the Ras/Raf/MEK/ERK pathway by Ca(2+), and calmodulin. Cell Signal. 2002; 14 (8): 649-654.
120. Abraham SJ, Nolet RP, Calvert RJ, et al. The hypervariable region of K-Ras4B is responsible for its specific interactions with calmodulin. Biochemistry. 2009; 48 (32): 7575-7583.
121. Lopez-Alcala C, Alvarez-Moya B, Villalonga P, et al. Identification of essential interacting elements in K-Ras/calmodulin binding and its role in K-Ras localization. J Biol Chem. 2008; 283 (16): 10621-10631.
122. Ashery U, Yizhar O, Rotblat B, et al. Nonconventional trafficking of Ras associated with Ras signal organization. Traffic. 2006; 7 (9): 119-126.
123. Wu LJ, Xu LR, Liao JM, et al. Both the C-terminal polylysine region and the farnesylation of K-RasB are important for its specific interaction with calmodulin. PloS one. 2011; 6 (7): e21929.
124. Sidhu RS, Clough RR, Bhullar RP. Ca2+/calmodulin binds and dissociates K-RasB from membrane. Biochem Biophys Res Commun. 2003; 304 (4): 655-660.
125. Aytuna AS, Gursoy A, Keskin O. Prediction of protein-protein interactions by combining structure and sequence conservation in protein interfaces. Bioinformatics. 2005; 21 (12): 2850-2855.
126. Ogmen U, Keskin O, Aytuna AS, et al. PRISM: protein interactions by structural matching. Nucleic Acids Res. 2005; 33. (Web Server issue): W331-336.
127. Tuncbag N, Gursoy A, Nussinov R, et al. Predicting protein-protein interactions on a proteome scale by matching evolutionary and structural similarities at interfaces using PRISM. Nat Protoc. 2011; 6 (9): 1341-1354.
128. Nussinov R, Ma B, Tsai CJ. A broad view of scaffolding suggests that scaffolding proteins can actively control regulation and signaling of multienzyme complexes through allostery. Biochim Biophys Acta. 2013; 1834 (5): 820-829.
129. Baouz S, Jacquet E, Bernardi A, et al. The N-terminal moiety of CDC25(Mm), a GDP/GTP exchange factor of Ras proteins, controls the activity of the catalytic domain. Modulation by calmodulin and calpain. J Biol Chem. 1997; 272 (10): 6671-6676.
130. Buchsbaum R, Telliez JB, Goonesekera S, et al. The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium. Mol Cell Biol. 1996; 16 (9): 4888-4896.
131. de Hoog CL, Fan WT, Goldstein MD, et al. Calmodulin-independent coordination of Ras and extracellular signal-regulated kinase activation by Ras-GRF2. Mol Cell Biol. 2000; 20 (8): 2727-2733.
132. Farnsworth CL, Freshney NW, Rosen LB, et al. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature. 1995; 376 (6540): 524-527.
133. Tian X, Rusanescu G, Hou W, et al. PDK1 mediates growth factor-induced Ral-GEF activation by a kinase-independent mechanism. EMBO J. 2002; 21 (6): 1327-1338.
134. Carragher NO, Fonseca BD, Frame MC. Calpain activity is generally elevated during transformation but has oncogene-specific biological functions. Neoplasia. 2004; 6 (1): 53-73.
135. Wang KL, Khan MT, Roufogalis BD. Identification and characterization of a calmodulin-binding domain in Ral-A, a Ras-related GTP-binding protein purified from human erythrocyte membrane. J Biol Chem. 1997; 272 (25): 16002-16009.
136. Park JB. Regulation of GTP-binding state in RalA through Ca2+ and calmodulin. Exp Mol Med. 2001; 33 (1): 54-58.
137. van der Weyden L, Adams DJ. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007; 1776 (1): 58-85.
138. Volodko N, Gordon M, Salla M, et al. RASSF tumor suppressor gene family: biological functions and regulation. FEBS Lett. 2014; 588 (16): 2671-2684.
139. Allen NP, Donninger H, Vos MD, et al. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene. 2007; 26 (42): 6203-6211.
140. Kumari G, Mahalingam S. Extracellular signal-regulated kinase 2 (ERK-2) mediated phosphorylation regulates nucleo-cytoplasmic shuttling and cell growth control of Ras-associated tumor suppressor protein, RASSF2. Exp Cell Res. 2009; 315 (16): 2775-2790.
141. Song H, Kim H, Lee K, et al. Ablation of Rassf2 induces bone defects and subsequent haematopoietic anomalies in mice. EMBO J. 2012; 31 (5): 1147-1159.
142. Akino K, Toyota M, Suzuki H, et al. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology. 2005; 129 (1): 156-169.
143. Kuznetsov S, Khokhlatchev AV. The growth and tumor suppressors NORE1A and RASSF1A are targets for calpain-mediated proteolysis. PloS one. 2008; 3 (12): e3997.
144. Schagdarsurengin U, Richter AM, Hornung J, et al. Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences. Mol Cancer. 2010; 9: 264.
145. Clark J, Freeman J, Donninger H. Loss of RASSF2 enhances tumorigencity of lung cancer cells and confers resistance to chemotherapy. Mol Biol Int. 2012; 2012: 705948.
146. Ikeda M, Kawata A, Nishikawa M, et al. Hippo pathway-dependent and -independent roles of RASSF6. Sci Signal. 2009; 2 (90): ra59.
147. Rodriguez-Viciana P, Sabatier C, McCormick F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol. 2004; 24 (11): 4943-4954.
148. Hamad NM, Elconin JH, Karnoub AE, et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Gene Dev. 2002; 16 (16): 2045-2057.
149. Rodriguez-Viciana P, Warne PH, Khwaja A, et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997; 89 (3): 457-467.
150. Lambert JM, Lambert QT, Reuther GW, et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat Cell Biol. 2002; 4 (8): 621-625.
151. Chang LC, Chiu HM, Shun CT, et al. Mutational profiles of different macroscopic subtypes of colorectal adenoma reveal distinct pathogenetic roles for KRAS, BRAF and PIK3CA. BMC Gastroenterol. 2014; 14 (1): 221.
152. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007; 7 (4): 295-308.
153. Nussinov R, Tsai CJ. Latent drivers expand the cancer mutational landscape. Curr Opin Struct Biol. 2015; 32: 25-32.
154. Tsai CJ, Nussinov R. The free energy landscape in translational science: how can somatic mutations result in constitutive oncogenic activation? Phys Chem Chem Phys. 2014; 16 (14): 6332-6341.
155. Tsai CJ, Nussinov R. A unified view of "how allostery works". PLoS Comput Biol. 2014; 10 (2): e1003394.
156. Nussinov R, Ma B, Tsai CJ, et al. Allosteric conformational barcodes direct signaling in the cell. Structure. 2013; 21 (9): 1509-1521.
157. Bardeesy N, Sharpless NE. RAS unplugged: negative feedback and oncogene-induced senescence. Cancer Cell. 2006; 10 (6): 451-453.
158. Cagnol S, Rivard N. Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition. Oncogene. 2013; 32 (5): 564-576.
159. Nussinov R, Jang H, Tsai CJ. Oligomerization and nanocluster organization render specificity. Biol Rev Camb Philos Soc. 2015; 90 (2): 587-598.
160. Nussinov R, Jang H. Dynamic multiprotein assemblies shape the spatial structure of cell signaling. Prog Biophys Mol Biol. 2014; 116 (2-3): 158-164.
161. Nussinov R, Tsai CJ, Mattos C. Pathway drug cocktail: targeting Ras signaling based on structural pathways. Trends Mol Med. 2013; 19 (11): 695-704.
162. Kar G, Keskin O, Gursoy A, et al. Allostery and population shift in drug discovery. Curr Opin Pharmacol. 2010; 10 (6): 715-722.
163. Greten FR. YAP1 takes over when oncogenic K-Ras slumbers. Cell. 2014; 158 (1): 11-12.
164. Kapoor A, Yao W, Ying H, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014; 158 (1): 185-197.
165. Shao DD, Xue W, Krall EB, et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell. 2014; 158 (1): 171-184.