Nonredundant functions for ras GTPase-activating proteins in tissue homeostasis

Science Signaling

Volumn 6, Issue 264, 2013, Pages

  King, Philip D ^a   Lubeck, Beth A ^a   Lapinski, Philip E ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GUANOSINE TRIPHOSPHATASE; RAS PROTEIN;

GENETIC ANALYSIS; HOMEOSTASIS; HUMAN; PHYSIOLOGY; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW;

ANIMALS; CELL MEMBRANE; HOMEOSTASIS; HUMANS; MICE; MODELS, BIOLOGICAL; NEUROFIBROMIN 1; P120 GTPASE ACTIVATING PROTEIN; PROTEIN STRUCTURE, TERTIARY; RAS GTPASE-ACTIVATING PROTEINS; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 84875158202     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2003669     Document Type: Review

References (147)

1. K. Wennerberg, K. L. Rossman, C. J. Der, The Ras superfamily at a glance. J. Cell Sci. 118, 843-846 (2005). (Pubitemid 40484876)
2. J. L. Bos, H. Rehmann, A. Wittinghofer, GEFs and GAPs: Critical elements in the control of small G proteins. Cell 129, 865-877 (2007). (Pubitemid 46802708)
3. L. Buday, J. Downward, Many faces of Ras activation. Biochim. Biophys. Acta 1786, 178-187 (2008).
4. L. Chang, M. Karin, Mammalian MAP kinase signalling cascades. Nature 410, 37-40 (2001). (Pubitemid 32225829)
5. S. Donovan, K. M. Shannon, G. Bollag, GTPase activating proteins: Critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602, 23-45 (2002). (Pubitemid 34311898)
6. M. R. Ahmadian, C. Kiel, P. Stege, K. Scheffzek, Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP. J. Mol. Biol. 329, 699-710 (2003). (Pubitemid 36629364)
7. K. Scheffzek, M. R. Ahmadian, W. Kabsch, L. Wiesmüller, A. Lautwein, F. Schmitz, A. Wittinghofer, The Ras-RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333-338 (1997). (Pubitemid 27450699)
8. M. R. Ahmadian, U. Hoffmann, R. S. Goody, A. Wittinghofer, Individual rate constants for the interaction of Ras proteins with GTPase-activating proteins determined by fluorescence spectroscopy. Biochemistry 36, 4535-4541 (1997). (Pubitemid 27180301)
9. Y. Pylayeva-Gupta, E. Grabocka, D. Bar-Sagi, RAS oncogenes: Weaving a tumorigenic web. Nat. Rev. Cancer 11, 761-774 (2011).
10. I. A. Prior, P. D. Lewis, C. Mattos, A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457-2467 (2012).
11. U. S. Vogel, R. A. Dixon, M. D. Schaber, R. E. Diehl, M. S. Marshall, E. M. Scolnick, I. S. Sigal, J. B. Gibbs, Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335, 90-93 (1988).
12. M. Trahey, G. Wong, R. Halenbeck, B. Rubinfeld, G. Martin, M. Ladner, C. Long, W. Crosier, K. Watt, K. Koths, et, Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242, 1697-1700 (1988). (Pubitemid 19022176)
13. D. A. Marchuk, A. M. Saulino, R. Tavakkol, M. Swaroop, M. R. Wallace, L. B. Andersen, A. L. Mitchell, D. H. Gutmann, M. Boguski, F. S. Collins, cDNA cloning of the type 1 neurofibromatosis gene: Complete sequence of the NF1 gene product. Genomics 11, 931-940 (1991).
14. R. Ballester, D. Marchuk, M. Boguski, A. Saulino, R. Letcher, M. Wigler, F. Collins, The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851-859 (1990). (Pubitemid 120035058)
15. G. A. Martin, D. Viskoohil, G. Bollag, P. C. Mc- Cabe, W. J. Crosier, H. Haubruck, L. Conroy, R. Clark, P. O'Connell, R. M. Cawthon, M. A. Innis, F. McCormick, The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843-849 (1990). (Pubitemid 120035057)
16. G. F. Xu, B. Lin, K. Tanaka, D. Dunn, D. Wood, R. Gesteland, R. White, R. Weiss, F. Tamanoi, The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63, 835-841 (1990). (Pubitemid 120035056)
17. G. F. Xu, P. O'Connell, D. Viskochil, R. Cawthon, M. Robertson, M. Culver, D. Dunn, J. Stevens, R. Gesteland, R. White, R. Weiss, The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599-608 (1990).
18. J. Kuriyan, D. Cowburn, Modular peptide recognition domains in eukaryotic signaling. Annu. Rev. Biophys. Biomol. Struct. 26, 259-288 (1997). (Pubitemid 27255374)
19. Y. M. Agazie, M. J. Hayman, Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling. Mol. Cell. Biol. 23, 7875-7886 (2003). (Pubitemid 37271483)
20. J. A. Cooper, A. Kashishian, In vivo binding properties of SH2 domains from GTPase-activating protein and phosphatidylinositol 3-kinase. Mol. Cell. Biol. 13, 1737-1745 (1993). (Pubitemid 23068112)
21. S. Ekman, E. R. Thuresson, C. H. Heldin, L. Rönnstrand, Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding. Oncogene 18, 2481-2488 (1999). (Pubitemid 29206161)
22. W. J. Fantl, J. A. Escobedo, G. A. Martin, C. W. Turck, M. del Rosario, F. McCormick, L. T. Williams, Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 69, 413-423 (1992).
23. A. Kazlauskas, C. Ellis, T. Pawson, J. A. Cooper, Binding of GAP to activated PDGF receptors. Science 247, 1578-1581 (1990).
24. B. Margolis, N. Li, A. Koch, M. Mohammadi, D. R. Hurwitz, A. Zilberstein, A. Ullrich, T. Pawson, J. Schlessinger, The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. EMBO J. 9, 4375-4380 (1990). (Pubitemid 120025994)
25. T. Grewal, R. Evans, C. Rentero, F. Tebar, L. Cubells, I. de Diego, M. F. Kirchhoff, W. E. Hughes, J. Heeren, K. A. Rye, F. Rinninger, R. J. Daly, A. Pol, C. Enrich, Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene 24, 5809-5820 (2005). (Pubitemid 43080072)
26. S. Vilá de Muga, P. Timpson, L. Cubells, R. Evans, T. E. Hayes, C. Rentero, A. Hegemann, M. Reverter, J. Leschner, A. Pol, F. Tebar, R. J. Daly, C. Enrich, T. Grewal, Annexin A6 inhibits Ras signalling in breast cancer cells. Oncogene 28, 363-377 (2009).
27. P. Pamonsinlapatham, R. Hadj-Slimane, Y. Lepelletier, B. Allain, M. Toccafondi, C. Garbay, F. Raynaud, p120-Ras GTPase activating protein (Ras- GAP): A multi-interacting protein in downstream signaling. Biochimie 91, 320-328 (2009).
28. S. V. Kulkarni, G. Gish, P. van der Geer, M. Henkemeyer, T. Pawson, Role of p120 Ras-GAP in directed cell movement. J. Cell Biol. 149, 457-470 (2000). (Pubitemid 30227161)
29. P. van der Geer, M. Henkemeyer, T. Jacks, T. Pawson, Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120- Gap. Mol. Cell. Biol. 17, 1840-1847 (1997). (Pubitemid 27133269)
30. I. D'Angelo, S. Welti, F. Bonneau, K. Scheffzek, A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. EMBO Rep. 7, 174-179 (2006).
31. S. Welti, S. Fraterman, I. D'Angelo, M. Wilm, K. Scheffzek, The sec14 homology module of neurofibromin binds cellular glycerophospholipids: Mass spectrometry and structure of a lipid complex. J. Mol. Biol. 366, 551-562 (2007). (Pubitemid 46136212)
32. I. B. Stowe, E. L. Mercado, T. R. Stowe, E. L. Bell, J. A. Oses-Prieto, H. Hernández, A. L. Burlingame, F. McCormick, A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev. 26, 1421-1426 (2012).
33. J. Lim, P. Yusoff, E. S. Wong, S. Chandramouli, D. H. Lao, C. W. Fong, G. R. Guy, The cysteine-rich sprouty translocation domain targets mitogenactivated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes. Mol. Cell. Biol. 22, 7953-7966 (2002). (Pubitemid 35217304)
34. A. Nonami, R. Kato, K. Taniguchi, D. Yoshiga, T. Taketomi, S. Fukuyama, M. Harada, A. Sasaki, A. Yoshimura, Spred-1 negatively regulates interleukin- 3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells. J. Biol. Chem. 279, 52543-52551 (2004). (Pubitemid 39656630)
35. S. Yarwood, D. Bouyoucef-Cherchalli, P. J. Cullen, S. Kupzig, The GAP1 family of GTPase-activating proteins: Spatial and temporal regulators of small GTPase signalling. Biochem. Soc. Trans. 34, 846-850 (2006). (Pubitemid 44796435)
36. P. J. Cullen, P. J. Lockyer, Integration of calcium and Ras signalling. Nat. Rev. Mol. Cell Biol. 3, 339-348 (2002). (Pubitemid 34619268)
37. M. Maekawa, S. Li, A. Iwamatsu, T. Morishita, K. Yokota, Y. Imai, S. Kohsaka, S. Nakamura, S. Hattori, A novel mammalian Ras GTPase-activating protein which has phospholipid-binding and Btk homology regions. Mol. Cell. Biol. 14, 6879-6885 (1994).
38. T. Yamamoto, T. Matsui, M. Nakafuku, A. Iwamatsu, K. Kaibuchi, A novel GTPase-activating protein for R-Ras. J. Biol. Chem. 270, 30557-30561 (1995). (Pubitemid 26005115)
39. P. J. Lockyer, S. Kupzig, P. J. Cullen, CAPRI regulates Ca(2+)-dependent inactivation of the Ras- MAPK pathway. Curr. Biol. 11, 981-986 (2001). (Pubitemid 32589191)
40. M. Allen, S. Chu, S. Brill, C. Stotler, A. Buckler, Restricted tissue expression pattern of a novel human rasGAP-related gene and its murine ortholog. Gene 218, 17-25 (1998). (Pubitemid 28434935)
41. G. E. Cozier, P. J. Lockyer, J. S. Reynolds, S. Kupzig, J. R. Bottomley, T. H. Millard, G. Banting, P. J. Cullen, GAP1IP4BP contains a novel group I pleckstrin homology domain that directs constitutive plasma membrane association. J. Biol. Chem. 275, 28261-28268 (2000).
42. G. E. Cozier, D. Bouyoucef, P. J. Cullen, Engineering the phosphoinositide-binding profile of a class I pleckstrin homology domain. J. Biol. Chem. 278, 39489-39496 (2003). (Pubitemid 37248506)
43. P. J. Lockyer, J. R. Bottomley, J. S. Reynolds, T. J. McNulty, K. Venkateswarlu, B. V. Potter, C. E. Dempsey, P. J. Cullen, Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BP PH domain directing plasma membrane targeting. Curr. Biol. 7, 1007-1010 (1997). (Pubitemid 28017081)
44. P. J. Lockyer, S. Wennström, S. Kupzig, K. Venkateswarlu, J. Downward, P. J. Cullen, Identification of the ras GTPase-activating protein GAP1(m) as a phosphatidylinositol-3,4,5- trisphosphate-binding protein in vivo. Curr. Biol. 9, 265-269 (1999).
45. S. A. Walker, S. Kupzig, D. Bouyoucef, L. C. Davies, T. Tsuboi, T. G. Bivona, G. E. Cozier, P. J. Lockyer, A. Buckler, G. A. Rutter, M. J. Allen, M. R. Philips, P. J. Cullen, Identification of a Ras GTPase-activating protein regulated by receptormediated Ca2+ oscillations. EMBO J. 23, 1749- 1760 (2004). (Pubitemid 38649638)
46. Q. Liu, S. A. Walker, D. Gao, J. A. Taylor, Y. F. Dai, R. S. Arkell, M. D. Bootman, H. L. Roderick, P. J. Cullen, P. J. Lockyer, CAPRI and RASAL impose different modes of information processing on Ras due to contrasting temporal filtering of Ca2+. J. Cell Biol. 170, 183-190 (2005). (Pubitemid 41043801)
47. S. Kupzig, D. Deaconescu, D. Bouyoucef, S. A. Walker, Q. Liu, C. L. Polte, O. Daumke, T. Ishizaki, P. J. Lockyer, A. Wittinghofer, P. J. Cullen, GAP1 family members constitute bifunctional Ras and Rap GTPase-activating proteins. J. Biol. Chem. 281, 9891-9900 (2006). (Pubitemid 43864521)
48. S. Kupzig, D. Bouyoucef-Cherchalli, S. Yarwood, R. Sessions, P. J. Cullen, The ability of GAP1IP4BP to function as a Rap1 GTPase-activating protein (GAP) requires its Ras GAP-related domain and an arginine finger rather than an asparagine thumb. Mol. Cell. Biol. 29, 3929-3940 (2009).
49. B. Sot, C. Kötting, D. Deaconescu, Y. Suveyzdis, K. Gerwert, A. Wittinghofer, Unravelling the mechanism of dual-specificity GAPs. EMBO J. 29, 1205-1214 (2010).
50. B. Sot, E. Behrmann, S. Raunser, A. Wittinghofer, Ras GTPase activating (RasGAP) activity of the dual specificity GAP protein Rasal requires colocalization and C2 domain binding to lipid membranes. Proc. Natl. Acad. Sci. U.S.A. 110, 111-116 (2013).
51. J. H. Kim, D. Liao, L. F. Lau, R. L. Huganir, Syn- GAP: A synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20, 683-691 (1998). (Pubitemid 28199048)
52. H. J. Chen, M. Rojas-Soto, A. Oguni, M. B. Kennedy, A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895-904 (1998). (Pubitemid 28247395)
53. V. Pena, M. Hothorn, A. Eberth, N. Kaschau, A. Parret, L. Gremer, F. Bonneau, M. R. Ahmadian, K. Scheffzek, The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction. EMBO Rep. 9, 350-355 (2008).
54. Z. Wang, C. P. Tseng, R. C. Pong, H. Chen, J. D. McConnell, N. Navone, J. T. Hsieh, The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2. J. Biol. Chem. 277, 12622-12631 (2002). (Pubitemid 34952621)
55. R. Zhang, X. He, W. Liu, M. Lu, J. T. Hsieh, W. Min, AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. J. Clin. Invest. 111, 1933-1943 (2003). (Pubitemid 38057738)
56. S. Noto, T. Maeda, S. Hattori, J. Inazawa, M. Imamura, M. Asaka, M. Hatakeyama, A novel human RasGAP-like gene that maps within the prostate cancer susceptibility locus at chromosome 1q25. FEBS Lett. 441, 127-131 (1998). (Pubitemid 29012386)
57. D. Díez, F. Sánchez-Jiménez, J. A. Ranea, Evolutionary expansion of the Ras switch regulatory module in eukaryotes. Nucleic Acids Res. 39, 5526-5537 (2011).
58. H. Chen, R. C. Pong, Z. Wang, J. T. Hsieh, Differential regulation of the human gene DAB2IP in normal and malignant prostatic epithelia: Cloning and characterization. Genomics 79, 573-581 (2002). (Pubitemid 34274299)
59. H. Zhang, R. Zhang, Y. Luo, A. D'Alessio, J. S. Pober, W. Min, AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation. J. Biol. Chem. 279, 44955- 44965 (2004). (Pubitemid 39430909)
60. H. Zhang, Y. He, S. Dai, Z. Xu, Y. Luo, T. Wan, D. Luo, D. Jones, S. Tang, H. Chen, W. C. Sessa, W. Min, AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. J. Clin. Invest. 118, 3904- 3916 (2008).
61. A. Weeks, N. Okolowsky, B. Golbourn, S. Ivanchuk, C. Smith, J. T. Rutka, ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells. Am. J. Pathol. 181, 662-674 (2012).
62. A. Bernards, GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim. Biophys. Acta 1603, 47-82 (2003). (Pubitemid 36262941)
63. B. Dasgupta, D. H. Gutmann, Neurofibromatosis 1: Closing the GAP between mice and men. Curr. Opin. Genet. Dev. 13, 20-27 (2003). (Pubitemid 36143923)
64. P. E. Lapinski, T. J. Bauler, E. J. Brown, E. D. Hughes, T. L. Saunders, P. D. King, Generation of mice with a conditional allele of the p120 Ras GTPase-activating protein. Genesis 45, 762-767 (2007). (Pubitemid 351158378)
65. P. J. Lockyer, S. Vanlingen, J. S. Reynolds, T. J. McNulty, R. F. Irvine, J. B. Parys, P. J. Cullen, Tissue-specific expression and endogenous subcellular distribution of the inositol 1,3,4,5-tetrakisphosphate- binding proteins GAP1(IP4BP) and GAP1(m). Biochem. Biophys. Res. Commun. 255, 421-426 (1999). (Pubitemid 29292275)
66. T. J. McNulty, A. J. Letcher, A. P. Dawson, R. F. Irvine, Tissue distribution of GAP1IP4BP and GAP1m: Two inositol 1,3,4,5-tetrakisphosphate- binding proteins. Cell. Signal. 13, 877-886 (2001). (Pubitemid 33139789)
67. J. Zhang, J. Guo, I. Dzhagalov, Y. W. He, An essential function for the calcium-promoted Ras inactivator in Fcgamma receptor-mediated phagocytosis. Nat. Immunol. 6, 911-919 (2005). (Pubitemid 43090446)
68. M. Henkemeyer, D. J. Rossi, D. P. Holmyard, M. C. Puri, G. Mbamalu, K. Harpal, T. S. Shih, T. Jacks, T. Pawson, Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377, 695-701 (1995).
69. P. E. Lapinski, S. Kwon, B. A. Lubeck, J. E. Wilkinson, R. S. Srinivasan, E. Sevick-Muraca, P. D. King, RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J. Clin. Invest. 122, 733-747 (2012).
70. T. Ichise, N. Yoshida, H. Ichise, H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice. Development 137, 1003-1013 (2010).
71. S. Anand, B. K. Majeti, L. M. Acevedo, E. A. Murphy, R. Mukthavaram, L. Scheppke, M. Huang, D. J. Shields, J. N. Lindquist, P. E. Lapinski, P. D. King, S. M. Weis, D. A. Cheresh, MicroRNA-132- mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat. Med. 16, 909-914 (2010).
72. P. E. Lapinski, Y. Qiao, C. H. Chang, P. D. King, A role for p120 RasGAP in thymocyte positive selection and survival of naive T cells. J. Immunol. 187, 151-163 (2011).
73. Y. Qiao, L. Zhu, H. Sofi, P. E. Lapinski, R. Horai, K. Mueller, G. L. Stritesky, X. He, H. S. Teh, D. L. Wiest, D. J. Kappes, P. D. King, K. A. Hogquist, P. L. Schwartzberg, D. B. Sant'Angelo, C. H. Chang, Development of promyelocytic leukemia zinc finger-expressing innate CD4 T cells requires stronger T-cell receptor signals than conventional CD4 T cells. Proc. Natl. Acad. Sci. U.S.A. 109, 16264-16269 (2012).
74. I. Eerola, L. M. Boon, J. B. Mulliken, P. E. Burrows, A. Dompmartin, S. Watanabe, R. Vanwijck, M. Vikkula, Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am. J. Hum. Genet. 73, 1240-1249 (2003). (Pubitemid 38037418)
75. N. Revencu, L. M. Boon, J. B. Mulliken, O. Enjolras, M. R. Cordisco, P. E. Burrows, P. Clapuyt, F. Hammer, J. Dubois, E. Baselga, F. Brancati, R. Carder, J. M. Quintal, B. Dallapiccola, G. Fischer, I. J. Frieden, M. Garzon, J. Harper, J. Johnson- Patel, C. Labrèze, L. Martorell, H. J. Paltiel, A. Pohl, J. Prendiville, I. Quere, D. H. Siegel, E. M. Valente, A. Van Hagen, L. Van Hest, K. K. Vaux, A. Vicente, L. Weibel, D. Chitayat, M. Vikkula, Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum. Mutat. 29, 959-965 (2008). (Pubitemid 351951290)
76. R. S. de Wijn, C. E. Oduber, C. C. Breugem, M. Alders, R. C. Hennekam, C. M. van der Horst, Phenotypic variability in a family with capillary malformations caused by a mutation in the RASA1 gene. Eur. J. Med. Genet. 55, 191-195 (2012).
77. R. M. Cawthon, R. Weiss, G. Xu, D. Viskochil, M. Culver, J. Stevens, M. Robertson, D. Dunn, R. Gesteland, P. O'Connell, R. White, A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193-201 (1990).
78. A. I. McClatchey, Neurofibromatosis. Annu. Rev. Pathol. 2, 191-216 (2007). (Pubitemid 46448064)
79. D. Viskochil, A. M. Buchberg, G. Xu, R. M. Cawthon, J. Stevens, R. K. Wolff, M. Culver, J. C. Carey, N. G. Copeland, N. A. Jenkins, R. White, P. O'Connell, Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187-192 (1990).
80. M. R. Wallace, D. Marchuk, L. Andersen, R. Letcher, H. Odeh, A. Saulino, J. Fountain, A. Brereton, J. Nicholson, A. Mitchell, et, Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science 249, 181-186 (1990).
81. E. M. Jouhilahti, S. Peltonen, A. M. Heape, J. Peltonen, The pathoetiology of neurofibromatosis 1. Am. J. Pathol. 178, 1932-1939 (2011).
82. E. Legius, D. A. Marchuk, F. S. Collins, T. W. Glover, Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat. Genet. 3, 122-126 (1993). (Pubitemid 23079793)
83. O. Maertens, H. Brems, J. Vandesompele, T. De Raedt, I. Heyns, T. Rosenbaum, S. De Schepper, A. De Paepe, G. Mortier, S. Janssens, F. Speleman, E. Legius, L. Messiaen, Comprehensive NF1 screening on cultured Schwann cells from neurofibromas. Hum. Mutat. 27, 1030-1040 (2006). (Pubitemid 44454056)
84. S. De Schepper, O. Maertens, T. Callens, J. M. Naeyaert, J. Lambert, L. Messiaen, Somatic mutation analysis in NF1 café au lait spots reveals two NF1 hits in the melanocytes. J. Invest. Dermatol. 128, 1050-1053 (2008). (Pubitemid 351374293)
85. H. Brems, C. Park, O. Maertens, A. Pemov, L. Messiaen, M. Upadhyaya, K. Claes, E. Beert, K. Peeters, V. Mautner, J. L. Sloan, L. Yao, C. C. Lee, R. Sciot, L. De Smet, E. Legius, D. R. Stewart, Glomus tumors in neurofibromatosis type 1: Genetic, functional, and clinical evidence of a novel association. Cancer Res. 69, 7393-7401 (2009).
86. E. Serra, T. Rosenbaum, U. Winner, R. Aledo, E. Ars, X. Estivill, H. G. Lenard, C. Lázaro, Schwann cells harbor the somatic NF1 mutation in neurofibromas: Evidence of two different Schwann cell subpopulations. Hum. Mol. Genet. 9, 3055-3064 (2000). (Pubitemid 32000779)
87. C. I. Brannan, A. S. Perkins, K. S. Vogel, N. Ratner, M. L. Nordlund, S. W. Reid, A. M. Buchberg, N. A. Jenkins, L. F. Parada, N. G. Copeland, Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019-1029 (1994). (Pubitemid 24145666)
88. T. Jacks, T. S. Shih, E. M. Schmitt, R. T. Bronson, A. Bernards, R. A. Weinberg, Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat. Genet. 7, 353-361 (1994). (Pubitemid 24204410)
89. A. D. Gitler, Y. Zhu, F. A. Ismat, M. M. Lu, Y. Yamauchi, L. F. Parada, J. A. Epstein, Nf1 has an essential role in endothelial cells. Nat. Genet. 33, 75-79 (2003). (Pubitemid 36068686)
90. F. A. Ismat, J. Xu, M. M. Lu, J. A. Epstein, The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice. J. Clin. Invest. 116, 2378-2384 (2006). (Pubitemid 44330136)
91. L. Q. Le, L. F. Parada, Tumor microenvironment and neurofibromatosis type I: Connecting the GAPs. Oncogene 26, 4609-4616 (2007). (Pubitemid 47067408)
92. Y. Zhu, P. Ghosh, P. Charnay, D. K. Burns, L. F. Parada, Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296, 920-922 (2002). (Pubitemid 34464899)
93. F. C. Yang, D. A. Ingram, S. Chen, Y. Zhu, J. Yuan, X. Li, X. Yang, S. Knowles, W. Horn, Y. Li, S. Zhang, Y. Yang, S. T. Vakili, M. Yu, D. Burns, K. Robertson, G. Hutchins, L. F. Parada, D. W. Clapp, Nf1-dependent tumors require a microenvironment containing Nf1+/- and c-kit-dependent bone marrow. Cell 135, 437-448 (2008).
94. L. Q. Le, T. Shipman, D. K. Burns, L. F. Parada, Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4, 453-463 (2009).
95. G. Bollag, D. W. Clapp, S. Shih, F. Adler, Y. Y. Zhang, P. Thompson, B. J. Lange, M. H. Freedman, F. McCormick, T. Jacks, K. Shannon, Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat. Genet. 12, 144-148 (1996). (Pubitemid 26051293)
96. D. A. Largaespada, C. I. Brannan, N. A. Jenkins, N. G. Copeland, Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nat. Genet. 12, 137-143 (1996). (Pubitemid 26051292)
97. D. T. Le, N. Kong, Y. Zhu, J. O. Lauchle, A. Aiyigari, B. S. Braun, E. Wang, S. C. Kogan, M. M. Le Beau, L. Parada, K. M. Shannon, Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 103, 4243-4250 (2004). (Pubitemid 38685370)
98. A. D. Gitler, Y. Kong, J. K. Choi, Y. Zhu, W. S. Pear, J. A. Epstein, Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia. Pediatr. Res. 55, 581-584 (2004). (Pubitemid 38405843)
99. Y.-Y. Zhang, T. A. Vik, J. W. Ryder, E. F. Srour, T. Jacks, K. Shannon, D. W. Clapp, Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines. J. Exp. Med. 187, 1893-1902 (1998). (Pubitemid 28262452)
100. S. Laycock-van Spyk, H. P. Jim, L. Thomas, G. Spurlock, L. Fares, S. Palmer-Smith, U. Kini, A. Saggar, M. Patton, V. Mautner, D. T. Pilz, M. Upadhyaya, Identification of five novel SPRED1 germline mutations in Legius syndrome. Clin. Genet. 80, 93-96 (2011).
101. E. Denayer, M. Chmara, H. Brems, A. M. Kievit, Y. van Bever, A. M. Van den Ouweland, R. Van Minkelen, A. de Goede-Bolder, R. Oostenbrink, P. Lakeman, E. Beert, T. Ishizaki, T. Mori, K. Keymolen, J. Van den Ende, E. Mangold, S. Peltonen, G. Brice, J. Rankin, K. Y. Van Spaendonck-Zwarts, A. Yoshimura, E. Legius, Legius syndrome in fourteen families. Hum. Mutat. 32, E1985-E1998 (2011).
102. G. Spurlock, E. Bennett, N. Chuzhanova, N. Thomas, H. P. Jim, L. Side, S. Davies, E. Haan, B. Kerr, S. M. Huson, M. Upadhyaya, SPRED1 mutations (Legius syndrome): Another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J. Med. Genet. 46, 431-437 (2009).
103. H. Brems, M. Chmara, M. Sahbatou, E. Denayer, K. Taniguchi, R. Kato, R. Somers, L. Messiaen, S. De Schepper, J. P. Fryns, J. Cools, P. Marynen, G. Thomas, A. Yoshimura, E. Legius, Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat. Genet. 39, 1120-1126 (2007). (Pubitemid 47340658)
104. E. Pasmant, A. Sabbagh, N. Hanna, J. Masliah- Planchon, E. Jolly, P. Goussard, P. Ballerini, F. Cartault, S. Barbarot, J. Landman-Parker, N. Soufir, B. Parfait, M. Vidaud, P. Wolkenstein, D. Vidaud, R. N. France, SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J. Med. Genet. 46, 425-430 (2009).
105. L. Messiaen, S. Yao, H. Brems, T. Callens, A. Sathienkijkanchai, E. Denayer, E. Spencer, P. Arn, D. Babovic-Vuksanovic, C. Bay, G. Bobele, B. H. Cohen, L. Escobar, D. Eunpu, T. Grebe, R. Greenstein, R. Hachen, M. Irons, D. Kronn, E. Lemire, K. Leppig, C. Lim, M. McDonald, V. Narayanan, A. Pearn, R. Pedersen, B. Powell, L. R. Shapiro, D. Skidmore, D. Tegay, H. Thiese, E. H. Zackai, R. Vijzelaar, K. Taniguchi, T. Ayada, F. Okamoto, A. Yoshimura, A. Parret, B. Korf, E. Legius, Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. J. Am. Med. Assoc. 302, 2111-2118 (2009).
106. R. Kato, A. Nonami, T. Taketomi, T. Wakioka, A. Kuroiwa, Y. Matsuda, A. Yoshimura, Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation. Biochem. Biophys. Res. Commun. 302, 767-772 (2003). (Pubitemid 36294039)
107. J. A. King, N. M. Corcoran, G. M. D'Abaco, A. F. Straffon, C. T. Smith, C. L. Poon, M. Buchert, S. i, N. E. Hall, P. Lock, C. M. Hovens, Eve-3: A liver enriched suppressor of Ras/MAPK signaling. J. Hepatol. 44, 758-767 (2006).
108. S. Iwashita, M. Kobayashi, Y. Kubo, Y. Hinohara, M. Sezaki, K. Nakamura, R. Suzuki-Migishima, M. Yokoyama, S. Sato, M. Fukuda, M. Ohba, C. Kato, E. Adachi, S. Y. Song, Versatile roles of RRas GAP in neurite formation of PC12 cells and embryonic vascular development. J. Biol. Chem. 282, 3413-3417 (2007). (Pubitemid 47084417)
109. L. Blanc, S. L. Ciciotte, B. Gwynn, G. J. Hildick- Smith, E. L. Pierce, K. A. Soltis, J. D. Cooney, B. H. Paw, L. L. Peters, Critical function for the Ras- GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis. Proc. Natl. Acad. Sci. U.S.A. 109, 12099-12104 (2012).
110. L. L. Peters, E. C. McFarland-Starr, B. G. Wood, J. E. Barker, Heritable severe combined anemia and thrombocytopenia in the mouse: Description of the disease and successful therapy. Blood 76, 745-754 (1990). (Pubitemid 20253290)
111. J. Zhang, H. F. Lodish, Endogenous K-ras signaling in erythroid differentiation. Cell Cycle 6, 1970-1973 (2007). (Pubitemid 47327883)
112. T. F. Westbrook, E. S. Martin, M. R. Schlabach, Y. Leng, A. C. Liang, B. Feng, J. J. Zhao, T. M. Roberts, G. Mandel, G. J. Hannon, R. A. Depinho, L. Chin, S. J. Elledge, A genetic screen for candidate tumor suppressors identifies REST. Cell 121, 837-848 (2005). (Pubitemid 40806416)
113. I. G. Kolfschoten, B. van Leeuwen, K. Berns, J. Mullenders, R. L. Beijersbergen, R. Bernards, P. M. Voorhoeve, R. Agami, A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 121, 849-858 (2005). (Pubitemid 40806417)
114. D. F. Calvisi, S. Ladu, E. A. Conner, D. Seo, J. T. Hsieh, V. M. Factor, S. S. Thorgeirsson, Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer. J. Hepatol. 54, 311-319 (2011).
115. H. Jin, X. Wang, J. Ying, A. H. Wong, Y. Cui, G. Srivastava, Z. Y. Shen, E. M. Li, Q. Zhang, J. Jin, S. Kupzig, A. T. Chan, P. J. Cullen, Q. Tao, Epigenetic silencing of a Ca(2+)-regulated Ras GTPaseactivating protein RASAL defines a new mechanism of Ras activation in human cancers. Proc. Natl. Acad. Sci. U.S.A. 104, 12353-12358 (2007). (Pubitemid 47206141)
116. M. Ohta, M. Seto, H. Ijichi, K. Miyabayashi, Y. Kudo, D. Mohri, Y. Asaoka, M. Tada, Y. Tanaka, T. Ikenoue, F. Kanai, T. Kawabe, M. Omata, Decreased expression of the RAS-GTPase activating protein RASAL1 is associated with colorectal tumor progression. Gastroenterology 136, 206- 216 (2009).
117. W. Bechtel, S. McGoohan, E. M. Zeisberg, G. A. Müller, H. Kalbacher, D. J. Salant, C. A. Müller, R. Kalluri, M. Zeisberg, Methylation determines fi- broblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544-550 (2010).
118. J. H. Kim, H. K. Lee, K. Takamiya, R. L. Huganir, The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J. Neurosci. 23, 1119-1124 (2003). (Pubitemid 36258890)
119. N. H. Komiyama, A. M. Watabe, H. J. Carlisle, K. Porter, P. Charlesworth, J. Monti, D. J. Strathdee, C. M. O'Carroll, S. J. Martin, R. G. Morris, T. J. O'Dell, S. G. Grant, SynGAP regulates ERK/ MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J. Neurosci. 22, 9721-9732 (2002). (Pubitemid 35332855)
120. L. E. Vazquez, H. J. Chen, I. Sokolova, I. Knuesel, M. B. Kennedy, SynGAP regulates spine formation. J. Neurosci. 24, 8862-8872 (2004). (Pubitemid 39362982)
121. I. Knuesel, A. Elliott, H. J. Chen, I. M. Mansuy, M. B. Kennedy, A role for synGAP in regulating neuronal apoptosis. Eur. J. Neurosci. 21, 611-621 (2005). (Pubitemid 40363497)
122. X. Guo, P. J. Hamilton, N. J. Reish, J. D. Sweatt, C. A. Miller, G. Rumbaugh, Reduced expression of the NMDA receptor-interacting protein Syn- GAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology 34, 1659-1672 (2009).
123. M. Muhia, J. Feldon, I. Knuesel, B. K. Yee, Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice. Behav. Neurosci. 123, 1114-1128 (2009).
124. M. Muhia, B. K. Yee, J. Feldon, F. Markopoulos, I. Knuesel, Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. Eur. J. Neurosci. 31, 529-543 (2010).
125. G. Krapivinsky, I. Medina, L. Krapivinsky, S. Gapon, D. E. Clapham, SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 43, 563-574 (2004). (Pubitemid 39094682)
126. G. Rumbaugh, J. P. Adams, J. H. Kim, R. L. Huganir, SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc. Natl. Acad. Sci. U.S.A. 103, 4344- 4351 (2006).
127. H. J. Carlisle, P. Manzerra, E. Marcora, M. B. Kennedy, SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J. Neurosci. 28, 13673-13683 (2008).
128. F. F. Hamdan, J. Gauthier, D. Spiegelman, A. Noreau, Y. Yang, S. Pellerin, S. Dobrzeniecka, M. Côté, E. Perreau-Linck, L. Carmant, G. D'Anjou, E. Fombonne, A. M. Addington, J. L. Rapoport, L. E. Delisi, M. O. Krebs, F. Mouaffak, R. Joober, L. Mottron, P. Drapeau, C. Marineau, R. G. Lafrenière, J. C. Lacaille, G. A. Rouleau, J. L. MichaudSynapse to Disease Group, Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N. Engl. J. Med. 360, 599-605 (2009).
129. W. Min, Y. Lin, S. Tang, L. Yu, H. Zhang, T. Wan, T. Luhn, H. Fu, H. Chen, AIP1 recruits phosphatase PP2A to ASK1 in tumor necrosis factor-induced ASK1-JNK activation. Circ. Res. 102, 840-848 (2008). (Pubitemid 351521590)
130. H. Zhang, H. Zhang, Y. Lin, J. Li, J. S. Pober, W. Min, RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation. J. Biol. Chem. 282, 14788-14796 (2007). (Pubitemid 47093366)
131. D. Luo, Y. He, H. Zhang, L. Yu, H. Chen, Z. Xu, S. Tang, F. Urano, W. Min, AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J. Biol. Chem. 283, 11905- 11912 (2008).
132. H. Chen, S. Toyooka, A. F. Gazdar, J. T. Hsieh, Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines. J. Biol. Chem. 278, 3121-3130 (2003). (Pubitemid 36801222)
133. H. Dote, S. Toyooka, K. Tsukuda, M. Yano, T. Ota, M. Murakami, M. Naito,
134. H. Dote, S. Toyooka, K. Tsukuda, M. Yano, M. Ouchida, H. Doihara, M. Suzuki, H. Chen, J. T. Hsieh, A. F. Gazdar, N. Shimizu, Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin. Cancer Res. 10, 2082-2089 (2004). (Pubitemid 38375570)
135. M. Yano, S. Toyooka, K. Tsukuda, H. Dote, M. Ouchida, T. Hanabata, M. Aoe, H. Date, A. F. Gazdar, N. Shimizu, Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers. Int. J. Cancer 113, 59-66 (2005). (Pubitemid 39507311)
136. H. Chen, S. W. Tu, J. T. Hsieh, Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J. Biol. Chem. 280, 22437-22444 (2005). (Pubitemid 40827899)
137. J. Min, A. Zaslavsky, G. Fedele, S. K. McLaughlin, E. E. Reczek, T. De Raedt, I. Guney, D. E. Strochlic, L. E. Macconaill, R. Beroukhim, R. T. Bronson, S. Ryeom, W. C. Hahn, M. Loda, K. Cichowski, An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat. Med. 16, 286-294 (2010).
138. D. Duggan, S. L. Zheng, M. Knowlton, D. Benitez, L. Dimitrov, F. Wiklund, C. Robbins, S. D. Isaacs, Y. Cheng, G. Li, J. Sun, B. L. Chang, L. Marovich, K. E. Wiley, K. Bälter, P. Stattin, H. O. Adami, M. Gielzak, G. Yan, J. Sauvageot, W. Liu, J. W. Kim, E. R. Bleecker, D. A. Meyers, B. J. Trock, A. W. Partin, P. C. Walsh, W. B. Isaacs, H. Grönberg, J. Xu, J. D. Carpten, Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J. Natl. Cancer Inst. 99, 1836-1844 (2007). (Pubitemid 351767196)
139. D. Xie, C. Gore, J. Zhou, R. C. Pong, H. Zhang, L. Yu, R. L. Vessella, W. Min, J. T. Hsieh, DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proc. Natl. Acad. Sci. U.S.A. 106, 19878-19883 (2009).
140. D. Xie, C. Gore, J. Liu, R. C. Pong, R. Mason, G. Hao, M. Long, W. Kabbani, L. Yu, H. Zhang, H. Chen, X. Sun, D. A. Boothman, W. Min, J. T. Hsieh, Role of DAB2IP in modulating epithelialto-mesenchymal transition and prostate cancer metastasis. Proc. Natl. Acad. Sci. U.S.A. 107, 2485-2490 (2010).
141. L. Yu, L. Qin, H. Zhang, Y. He, H. Chen, J. S. Pober, G. Tellides, W. Min, AIP1 prevents graft arteriosclerosis by inhibiting interferon-©- dependent smooth muscle cell proliferation and intimal expansion. Circ. Res. 109, 418-427 (2011).
142. S. Gretarsdottir, A. F. Baas, G. Thorleifsson, H. Holm, M. den Heijer, J. P. de Vries, S. E. Kranendonk, C. J. Zeebregts, S. M. van Sterkenburg, R. H. Geelkerken, A. M. van Rij, M. J. Williams, A. P. Boll, J. P. Kostic, A. Jonasdottir, A. Jonasdottir, G. B. Walters, G. Masson, P. Sulem, J. Saemundsdottir, M. Mouy, K. P. Magnusson, G. Tromp, J. R. Elmore, N. Sakalihasan, R. Limet, J. O. Defraigne, R. E. Ferrell, A. Ronkainen, Y. M. Ruigrok, C. Wijmenga, D. E. Grobbee, S. H. Shah, C. B. Granger, A. A. Quyyumi, V. Vaccarino, R. S. Patel, A. M. Zafari, A. I. Levey, H. Austin, D. Girelli, P. F. Pignatti, O. Olivieri, N. Martinelli, G. Malerba, E. Trabetti, L. C. Becker, D. M. Becker, M. P. Reilly, D. J. Rader, T. Mueller, B. Dieplinger, M. Haltmayer, S. Urbonavicius, B. Lindblad, A. Gottsäter, E. Gaetani, R. Pola, P. Wells, M. Rodger, M. Forgie, N. Langlois, J. Corral, V. Vicente, J. Fontcuberta, F. España, N. Grarup, T. Jørgensen, D. R. Witte, T. Hansen, O. Pedersen, K. K. Aben, J. de Graaf, S. Holewijn, L. Folkersen, A. Franco-Cereceda, P. Eriksson, D. A. Collier, H. Stefansson, V. Steinthorsdottir, T. Rafnar, E. M. Valdimarsson, H. B. Magnadottir, S. Sveinbjornsdottir, I. Olafsson, M. K. Magnusson, R. Palmason, V. Haraldsdottir, K. Andersen, P. T. Onundarson, G. Thorgeirsson, L. A. Kiemeney, J. T. Powell, D. J. Carey, H. Kuivaniemi, J. S. Lindholt, G. T. Jones, A. Kong, J. D. Blankensteijn, S. E. Matthiasson, U. Thorsteinsdottir, K. Stefansson, Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm. Nat. Genet. 42, 692-697 (2010).
143. N. Fehrenbacher, D. Bar-Sagi, M. Philips, Ras/ MAPK signaling from endomembranes. Mol. Oncol. 3, 297-307 (2009).
144. S. Li, S. Nakamura, S. Hattori, Activation of R-Ras GTPase by GTPase-activating proteins for Ras, Gap1(m), and p120GAP. J. Biol. Chem. 272, 19328-19332 (1997). (Pubitemid 27337726)
145. B. Dasgupta, Y. Yi, D. Y. Chen, J. D. Weber, D. H. Gutmann, Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 65, 2755-2760 (2005). (Pubitemid 40490077)
146. W. F. Khalaf, F. C. Yang, S. Chen, H. White, W. Bessler, D. A. Ingram, D. W. Clapp, K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells. J. Immunol. 178, 2527-2534 (2007). (Pubitemid 46233454)
147. E. M. Jouhilahti, S. Peltonen, A. M. Heape, J. Peltonen, The pathoetiology of neurofibromatosis 1. Am. J. Pathol. 178, 1932-1939 (2011).