Hyperactive Ras in developmental disorders and cancer

Nature Reviews Cancer

Volumn 7, Issue 4, 2007, Pages 295-308

  Schubbert, Suzanne ^a   Shannon, Kevin ^a,b   Bollag, Gideon ^c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c PLEXXIKON INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

B RAF KINASE; GUANOSINE TRIPHOSPHATE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; RAF PROTEIN; RAS PROTEIN; SOS PROTEIN;

AMINO ACID SUBSTITUTION; CANCER; CARCINOGENESIS; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; DEVELOPMENTAL DISORDER; GENE ACTIVATION; GENE CONTROL; GENE EXPRESSION; GENE INACTIVATION; GENE MUTATION; HUMAN; JUVENILE MYELOMONOCYTIC LEUKEMIA; LEOPARD SYNDROME; MISSENSE MUTATION; NEUROFIBROMATOSIS; NONHUMAN; NOONAN SYNDROME; ONCOGENE H RAS; ONCOGENE K RAS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION;

CHILD, PRESCHOOL; DEVELOPMENTAL DISABILITIES; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; GENE EXPRESSION REGULATION; GENES, RAS; GERM-LINE MUTATION; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; MITOGEN-ACTIVATED PROTEIN KINASES; MODELS, MOLECULAR; NEOPLASMS; PROTEIN-TYROSINE-PHOSPHATASE; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS C-RAF; SIGNAL TRANSDUCTION;

EID: 33947594129     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc2109     Document Type: Review

References (148)

1. Bourne, H. R., Sanders, D. A. & McCormick, F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125-132 (1990).
2. Bourne, H. R., Sanders, D. A. & McCormick, F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349, 117-127 (1991).
3. Vetter, I. R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299-1304 (2001).
4. Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593-604 (2001).
5. Tartaglia, M. & Gelb, B. D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45-68 (2005).
6. Bentires-Alj, M., Kontaridis, M. I. & Neel, B. G. Stops along the RAS pathway in human genetic disease. Nature Med. 12, 283-285 (2006).
7. Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37, 1038-1040 (2005). This study, demonstrating heterozygous mutations in HRAS in 12 out of 13 individuals with Costello syndrome, is the first report of a germline RAS mutation as the cause of a human disease.
8. Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D. & Neel, B. G. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J. Biol. Chem. 281, 6785-6792 (2006).
9. Rodriguez-Viciana, P. et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287-1290 (2006).
10. Niihori, T. et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genet. 38, 294-296 (2006). References 9 and 10 report BRAF and MEK1 and 2 mutations in CFC syndrome and establish the Raf-MEK-ERK kinase cascade as a critical downstream effector pathway of Ras in development.
11. Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nature Genet. 38, 331-336 (2006). This study identified novel germline KRAS mutations in Noonan and CFC syndromes and demonstrates that the encoded mutant proteins are functionally and biochemically hyperactive relative to wild-type KRAS, but less potent than oncogenic KRAS.
12. Roberts, A. E. et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genet. 39, 70-74 (2006).
13. Tartaglia, M. et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genet. 39, 75-79 (2006). References 12 and 13 report novel germline SOS1 mutations in ∼10% of Noonan syndrome patients, which establishes an important role of this GNEF in development, and provokes speculation of SOS1 as a proto-oncogene.
14. Tartaglia, M. et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am. J. Hum. Genet. 78, 279-290 (2006).
15. Boguski, M. & McCormick, F. Proteins regulating Ras and its relatives. Nature 366, 643-653 (1993).
16. Donovan, S., Shannon, K. M. & Bollag, G. GTPase activating poteins: critical regulators of intracellular signaling. BBA Rev. Cancer 1602, 23-45 (2002).
17. Mitin, N., Rossman, K. L. & Der, C. J. Signaling interplay in Ras superfamily function. Curr. Biol. 15, R563-R574 (2005).
18. Repasky, G. A., Chenette, E. J. & Der, C. J. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol. 14, 639-647 (2004).
19. Muroya, K., Hattori, S. & Nakamura, S. Nerve growth factor induces rapid accumulation of the GTP-bound form of p21ras in rat pheochromocytoma PC12 cells. Oncogene 7, 277-281 (1992).
20. Heasley, L. E. & Johnson, G. L. The β-PDGF receptor induces neuronal differentiation of PC12 cells. Mol. Biol. Cell 3, 545-553 (1992).
21. Traverse, S., Gomez, N., Paterson, H., Marshall, C. & Cohen, P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem. J. 288, 351-355 (1992).
22. Nguyen, T. T. et al. Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor. J. Biol. Chem. 268, 9803-9810 (1993).
23. Marshall, C. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179-185 (1995).
24. Yordy, J. S. & Muise-Helmericks, R. C. Signal transduction and the Ets family of transcription factors. Oncogene 19, 6503-6513 (2000).
25. Pruitt, K. & Der, C. J. Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett. 171, 1-10 (2001).
26. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527-532 (1994).
27. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931-943 (2000).
28. Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921-929 (2005).
29. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489-501 (2002).
30. Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y. & Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Rev. Drug Discov. 4, 988-1004 (2005).
31. Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867-871 (2002).
32. Wolthuis, R. M. & Bos, J. L. Ras caught in another affair: the exchange factors for Ral. Curr. Opin. Genet. Dev. 9, 112-117 (1999).
33. Gonzalez-Garcia, A. et al. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219-226 (2005).
34. Lim, K. H. et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7, 533-545 (2005).
35. 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).
36. Shibatohge, M. et al. Identification of PLC210, a Caenorhabditis elegans phospholipase C, as a putative effector of Ras. J. Biol. Chem. 273, 6218-6222 (1998).
37. Song, C. et al. Regulation of a novel human phospholipase C, PLCε, through membrane targeting by Ras. J. Biol. Chem. 276, 2752-2757 (2001).
38. Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase C(ε): a novel Ras effector. EMBO J. 20, 743-754 (2001).
39. Gibbs, J. B. & Oliff, A. The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu. Rev. Pharmacol. Toxicol. 37, 143-166 (1997).
40. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nature Rev. Cancer 3, 11-22 (2003).
41. 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).
42. Koera, K. et al. K-ras is essential for the development of the mouse embryo. Oncogene 15, 1151-1159 (1997).
43. Khalaf, W. F. et al. K-Ras is essential for normal fetal liver erythropoiesis. Blood 105, 3538-3541 (2005).
44. 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).
45. 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).
46. Mor, A. & Philips, M. R. Compartmentalized Ras/MAPK signaling. Annu. Rev. Immunol. 24, 771-800 (2006).
47. Hingorani, S. R. & Tuveson, D. A. Ras redux: rethinking how and where Ras acts. Curr. Opin. Genet. Dev. 13, 6-13 (2003).
48. Plowman, S. J. & Hancock, J. F. Ras signaling from plasma membrane and endomembrane microdomains. Biochim. Biophys. Acta 1746, 274-283 (2005).
49. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343-350 (2002).
50. 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).
51. 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).
52. 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).
53. 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).
54. 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).
55. Jura, N., Scotto-Lavino, E., Sobczyk, A. & Bar-Sagi, D. Differential modification of Ras proteins by ubiquitination. Mol. Cell 21, 679-687 (2006).
56. Bos, J. L. ras oncogenes in human cancer: a review. Cancer Res. 49, 4682-4689 (1989).
57. Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542-545 (1987).
58. 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).
59. 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).
60. Franken, S. M. et al. Three-dimensional structures and properties of a transforming and a nontransforming glycine-12 mutant of p21H-ras. Biochemistry 32, 8411-8420 (1993).
61. Colby, W. W., Hayflick, J. S., Clark, S. G. & Levinson, A. D. Biochemical characterization of polypeptides encoded by mutated human Ha-ras1 genes. Mol. Cell. Biol. 6, 730-734 (1986).
62. Marshall, M. S. The effector interactions of p21ras. Trends Biochem. Sci. 18, 250-254 (1993).
63. White, M. A. et al. Multiple Ras functions can contribute to mammalian cell transformation. Cell 80, 533-541 (1995).
64. Joneson, T., White, M. A., Wigler, M. H. & Bar-Sagi, D. Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS. Science 271, 810-812 (1996).
65. Khosravi-Far, R. et al. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol. Cell. Biol. 16, 3923-3933 (1996).
66. Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045-2057 (2002).
67. 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).
68. Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Biological properties of human c-Haras1 genes mutated at codon 12. Nature 312, 71-75 (1984).
69. 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).
70. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111-1116 (2001).
71. Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111-120 (2003).
72. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375-387 (2004).
73. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437-450 (2003).
74. Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112-3126 (2003).
75. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427-1429. (1995).
76. Braun, B. S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597-602 (2004).
77. Chan, I. T. et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J. Clin. Invest. 113, 528-538 (2004).
78. Sansom, O. J. et al. Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo. Proc. Natl Acad. Sci. USA 103, 14122-14127 (2006).
79. Downward, J. Signal transduction. Prelude to an anniversary for the RAS oncogene. Science 314, 433-434 (2006).
80. Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nature Rev. Cancer 3, 459-465 (2003).
81. Lazaro, C., Ravella, A., Gaona, A., Volpini, V. & Estivill, X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N. Engl. J. Med. 331, 1403-1407 (1994).
82. Poyhonen, M., Kytola, S. & Leisti, J. Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland. J. Med. Genet. 37, 632-636 (2000).
83. 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).
84. 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).
85. Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187-192 (1990).
86. Xu, G. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599-608 (1990).
87. 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).
88. Ingram, D. A. et al. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J. Exp. Med. 191, 181-188 (2000).
89. Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K. & Parada, L. F. Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920-922. (2002).
90. +/- mast cells. J. Clin. Invest. 112, 1851-1861 (2003).
91. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465-468 (2001).
92. Mohi, M. G. & Neel, B. G. The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17, 23-30 (2007).
93. Neel, B. G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284-293 (2003).
94. Qu, C. K. Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochim. Biophys. Acta 1592, 297-301 (2002).
95. Yang, W. et al. An Shp2/SFK/Ras/Erk signaling pathway controls trophoblast stem cell survival. Dev. Cell 10, 317-327 (2006).
96. Shi, Z. Q., Yu, D. H., Park, M., Marshall, M. & Feng, G. S. Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Mol. Cell. Biol. 20, 1526-1536 (2000).
97. Frearson, J. A. & Alexander, D. R. The phosphotyrosine phosphatase SHP-2 participates in a multimeric signaling complex and regulates T cell receptor (TCR) coupling to the Ras/mitogen-activated protein kinase (MAPK) pathway in Jurkat T cells. J. Exp. Med. 187, 1417-1426 (1998).
98. Gadina, M., Stancato, L. M., Bacon, C. M., Larner, A. C. & O'Shea, J. J. Involvement of SHP-2 in multiple aspects of IL-2 signaling: evidence for a positive regulatory role. J. Immunol. 160, 4657-4661 (1998).
99. Bennett, A. M., Tang, T. L., Sugimoto, S., Walsh, C. T. & Neel, B. G. Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor β to Ras. Proc. Natl Acad. Sci. USA 91, 7335-7339 (1994).
100. Cleghon, V. et al. Opposing actions of CSW and RasGAP modulate the strength of Torso RTK signaling in the Drosophila terminal pathway. Mol. Cell 2, 719-727. (1998).
101. Klinghoffer, R. A. & Kazlauskas, A. Identification of a putative Syp substrate, the PDGF β receptor. J. Biol. Chem. 270, 22208-22217 (1995).
102. Agazie, Y. M. & Hayman, M. J. Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Mol. Cell. Biol. 23, 7875-7886 (2003).
103. Hanafusa, H., Torii, S., Yasunaga, T., Matsumoto, K. & Nishida, E. Shp2, an SH2-containing proteintyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty. J. Biol. Chem. 279, 22992-22995 (2004).
104. Jarvis, L. A., Toering, S. J., Simon, M. A., Krasnow, M. A. & Smith-Bolton, R. K. Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases. Development 133, 1133-1142 (2006).
105. Zhang, S. Q. et al. Shp2 regulates Src family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 13, 341-355 (2004).
106. Ren, Y. et al. Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J. Biol. Chem. 279, 8497-8505 (2004).
107. 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). This study presents extensive biochemical analysis of a large panel of mutant SHP2 proteins associated with Noonan syndrome and leukaemia and demonstrates that mutations in PTPN11 can cause disease by multiple mechanisms, which include increasing SHP2 basal activation, and affecting SH2-domain binding to phosphotyrosyl ligands, and/or substrate specificity.
108. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148-150 (2003).
109. Tartaglia, M. et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104, 307-313 (2004).
110. Loh, M. L. et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103, 2325-2331 (2004).
111. Bentires-Alj, M. et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816-8820 (2004).
112. 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). The authors develop an elegant knock-in mouse model of Noonan syndrome that reveals the cell specific effects of expressing a Noonan syndrome-associated mutant SHP2 protein during development.
113. Gorlin, R. J., Anderson, R. C. & Blaw, M. Multiple lentigenes syndrome. Am. J. Dis. Child. 117, 652-662 (1969).
114. Hanna, N. et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 580, 2477-2482 (2006).
115. Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D. & Rauen, K. A. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am. J. Med. Genet. A 140, 8-16 (2006).
116. Gripp, K. W. et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am. J. Med. Genet. A 140, 1-7 (2006).
117. Kerr, B. et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J. Med. Genet. 43, 401-405 (2006).
118. Zampino, G. et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum. Mutat. 28, 265-272 (2007).
119. Proud, C. Guanine nucleotides, protein phosphorylation and the control of translation. Trends Biochem. Sci. 12, 73-77 (1986).
120. Carta, C. et al. Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. Am. J. Hum. Genet. 79, 129-135 (2006).
121. Zenker, M. et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J. Med. Genet. 44, 131-135 (2006).
122. Quilliam, L. A. et al. Biological and structural characterization of a Ras transforming mutation at the phenylalanine-156 residue, which is conserved in all members of the Ras superfamily. Proc. Natl Acad. Sci. USA 92, 1272-1276 (1995).
123. Roberts, A. et al. The cardio-facio-cutaneous (CFC) syndrome: a review. J. Med. Genet. (2006).
124. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002).
125. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nature Rev. Mol. Cell Biol. 5, 875-885 (2004).
126. Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313-319 (2004).
127. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116, 855-867 (2004). This study presents the first crystal structure of the BRAF kinase domain and the authors interrogate the biochemical properties of a panel of cancer-associated BRAF mutant proteins, some of which are kinase impaired and signal to ERK through a new mechanism involving Raf.
128. Pollock, P. M. et al. High frequency of BRAF mutations in nevi. Nature Genet. 33, 19-20 (2003).
129. Yazdi, A. S. et al. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J. Invest. Dermatol. 121, 1160-1162 (2003).
130. Dankort, D. et al. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 21, 379-384 (2007).
131. Solit, D. B. et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358-362 (2006).
132. King, A. J. et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66, 11100-11105 (2006).
133. Margarit, S. M. et al. Structural evidence for feedback activation by Ras. GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112, 685-695 (2003).
134. Sondermann, H. et al. Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell 119, 393-405 (2004).
135. Friedman, A. & Perrimon, N. Genetic screening for signal transduction in the era of network biology. Cell 128, 225-231 (2007).
136. Friedman, A. & Perrimon, N. A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature 444, 230-234 (2006).
137. Li, Z. et al. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nature Genet. 37, 613-619 (2005).
138. Neal, S. E., Eccleston, J. F., Hall, A. & Webb, M. R. Kinetic analysis of the hydrolysis of GTP by p21N-ras. The basal GTPase mechanism. J. Biol. Chem. 263, 19718-19722 (1988).
139. John, J., Frech, M. & Wittinghofer, A. Biochemical properties of Ha-ras encoded p21 mutants and mechanism of the autophosphorylation reaction. J. Biol. Chem. 263, 11792-11799 (1988).
140. 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).
141. 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).
142. Lauchle, J. O., Braun, B. S., Loh, M. L. & Shannon, K. Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatr. Blood Cancer 46, 579-585 (2006).
143. Chan, R. J. & Feng, G. S. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109, 862-867 (2006).
144. Tartaglia, M., Niemeyer, C. M., Shannon, K. M. & Loh, M. L. SHP-2 and myeloid malignancies. Curr. Opin. Hematol. 11, 44-50 (2004).
145. Mohi, M. G. et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by SHP2 (PTPN11) mutations. Cancer Cell 7, 179-191 (2005).
146. Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311-317 (2005).
147. Le, D. T. et al. Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 103, 4243-4250 (2004).
148. Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355-358 (2004).