Ubiquitination of K-Ras enhances activation and facilitates binding to select downstream effectors

Science Signaling

Volumn 4, Issue 163, 2011, Pages

  Sasaki, Atsuo T ^a   Carracedo, Arkaitz ^a,b   Locasale, Jason W ^a   Anastasiou, Dimitrios ^a   Takeuchi, Koh ^a,c   Kahoud, Emily Rose ^a   Haviv, Sasson ^a   Asara, John M ^a   Pandolfi, Pier Paolo ^a   Cantley, Lewis C ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b CIC BIOGUNE   (Spain)

^c NATIONAL INSTITUTE OF ADVANCED INDUSTRIAL SCIENCE AND TECHNOLOGY AIST   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCINE; GUANINE NUCLEOTIDE BINDING PROTEIN; H RAS PROTEIN; K RAS PROTEIN; LYSINE; MUTANT PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; RAF PROTEIN; UNCLASSIFIED DRUG; VALINE; GUANOSINE TRIPHOSPHATE; KRAS PROTEIN, HUMAN; ONCOPROTEIN; RAS PROTEIN;

ARTICLE; CARCINOGENICITY; CONTROLLED STUDY; ENZYME ACTIVATION; HUMAN; HUMAN CELL; MASS SPECTROMETRY; MOLECULAR MECHANICS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN MOTIF; UBIQUITINATION; WILD TYPE; AFFINITY CHROMATOGRAPHY; AMINO ACID SEQUENCE; CELL LINE; CHEMICAL STRUCTURE; METABOLISM; MOLECULAR GENETICS; PHYSIOLOGY; TANDEM MASS SPECTROMETRY;

AMINO ACID SEQUENCE; CELL LINE; CHROMATOGRAPHY, AFFINITY; GUANOSINE TRIPHOSPHATE; HUMANS; LYSINE; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN BINDING; PROTO-ONCOGENE PROTEINS; RAF KINASES; RAS PROTEINS; TANDEM MASS SPECTROMETRY; UBIQUITINATION;

EID: 79952551201     PISSN: 19450877     EISSN: 19379145     Source Type: Journal    
DOI: 10.1126/scisignal.2001518     Document Type: Article

References (32)

1. A. E. Karnoub, R. A. Weinberg, Ras oncogenes: Split personalities. Nat. Rev. Mol. Cell Biol. 9, 517-531 (2008).
2. K. Wennerberg, K. L. Rossman, C. J. Der, The Ras superfamily at a glance. J. Cell Sci. 118, 843-846 (2005).
3. I. R. Vetter, A. Wittinghofer, The guanine nucleotide-binding switch in three dimensions. Science 294, 1299-1304 (2001).
4. S. Edkins, S.O'Meara, A. Parker, C. Stevens, M. Reis, S. Jones, C. Greenman, H.Davies, G. Dalgliesh, S. Forbes, C. Hunter, R. Smith, P. Stephens, P. Goldstraw, A. Nicholson, T. L. Chan, V. E. Velculescu, S. T. Yuen, S. Y. Leung, M. R. Stratton, P. A. Futreal, Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol. Ther. 5, 928-932 (2006).
5. S. Schubbert, G. Bollag, N. Lyubynska, H. Nguyen, C. P. Kratz, M. Zenker, C. M. Niemeyer, A. Molven, K. Shannon, Biochemical and functional characterization of germ line KRAS mutations. Mol. Cell. Biol. 27, 7765-7770 (2007).
6. E. Denayer, A. Parret, M. Chmara, S. Schubbert, A. Vogels, K. Devriendt, J. P. Frijns, V. Rybin, T. J. de Ravel, K. Shannon, J. Cools, K. Scheffzek, E. Legius, Mutation analysis in Costello syndrome: Functional and structural characterization of the HRAS p.Lys117Arg mutation. Hum. Mutat. 29, 232-239 (2008).
7. M. Janakiraman, E. Vakiani, Z. Zeng, C. A. Pratilas, B. S. Taylor, D. Chitale, E. Halilovic, M. Wilson, K. Huberman, J. C. Ricarte Filho, Y. Persaud, D. A. Levine, J. A. Fagin, S. C. Jhanwar, J. M. Mariadason, A. Lash, M. Ladanyi, L. B. Saltz, A. Heguy, P. B. Paty, D. B. Solit, Genomic and biological characterization of exon 4 KRAS mutations in human cancer. Cancer Res. 70, 5901-5911 (2010).
8. D. K. Morrison, R. J. Davis, Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu. Rev. Cell Dev. Biol. 19, 91-118 (2003).
9. E. A. Elion, The Ste5p scaffold. J. Cell Sci. 114, 3967-3978 (2001).
10. W. Li, M. Han, K. L. Guan, The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev. 14, 895-900 (2000).
11. N. Jura, E. Scotto-Lavino, A. Sobczyk, D. Bar-Sagi, Differential modification of Ras proteins by ubiquitination. Mol. Cell 21, 679-687 (2006).
12. L. Xu, V. Lubkov, L. J. Taylor, D. Bar-Sagi, Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr. Biol. 20, 1372-1377 (2010).
13. S. E. Kim, J. Y. Yoon, W. J. Jeong, S. H. Jeon, Y. Park, J. B. Yoon, Y. N. Park, H. Kim, K. Y. Choi, H-Ras is degraded by Wnt/β-catenin signaling via β-TrCP-mediated polyubiquitylation. J. Cell Sci. 122, 842-848 (2009).
14. M. Spoerner, C. Herrmann, I. R. Vetter, H. R. Kalbitzer, A. Wittinghofer, Dynamic properties of the Ras switch I region and its importance for binding to effectors. Proc. Natl. Acad. Sci. U.S.A. 98, 4944-4949 (2001).
15. J. S. Thrower, L. Hoffman, M. Rechsteiner, C. M. Pickart, Recognition of the polyubiquitin proteolytic signal. EMBO J. 19, 94-102 (2000).
16. J. Miller, C. Gordon, The regulation of proteasome degradation by multi-ubiquitin chain binding proteins. FEBS Lett. 579, 3224-3230 (2005).
17. T. Sjöblom, S. Jones, L. D. Wood, D. W. Parsons, J. Lin, T. D. Barber, D. Mandelker, R. J. Leary, J. Ptak, N. Silliman, S. Szabo, P. Buckhaults, C. Farrell, P. Meeh, S. D. Markowitz, J. Willis, D. Dawson, J. K. Willson, A. F. Gazdar, J. Hartigan, L. Wu, C. Liu, G. Parmigiani, B. H. Park, K. E. Bachman, N. Papadopoulos, B. Vogelstein, K. W. Kinzler, V. E. Velculescu, The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274 (2006).
18. S. R. Sloan, E. W. Newcomb, A. Pellicer, Neutron radiation can activate K-ras via a point mutation in codon 146 and induces a different spectrum of ras mutations than does gamma radiation. Mol. Cell. Biol. 10, 405-408 (1990).
19. S. Orita, T. Higashi, Y. Kawasaki, A. Harada, H. Igarashi, T. Monden, H. Morimoto, T. Shimano, T. Mori, J. Miyoshi, A novel point mutation at codon 146 of the K-ras gene in a human colorectal cancer identified by the polymerase chain reaction. Virus Genes 5, 75-79 (1991).
20. G. Zampino, F. Pantaleoni, C. Carta, G. Cobellis, I. Vasta, C. Neri, E. A. Pogna, E. De Feo, A. Delogu, A. Sarkozy, F. Atzeri, A. Selicorni, K. A. Rauen, C. S. Cytrynbaum, R. Weksberg, B. Dallapiccola, A. Ballabio, B. D. Gelb, G. Neri, M. Tartaglia, Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum. Mutat. 28, 265-272 (2007).
21. M. V. Milburn, L. Tong, A. M. deVos, A. Brünger, Z. Yamaizumi, S. Nishimura, S. H. Kim, Molecular switch for signal transduction: Structural differences between active and inactive forms of protooncogenic ras proteins. Science 247, 939-945 (1990).
22. E. F. Pai, U. Krengel, G. A. Petsko, R. S. Goody, W. Kabsch, A. Wittinghofer, Refined crystal structure of the triphosphate conformation of H-ras p21 at 1.35 Å resolution: Implications for the mechanism of GTP hydrolysis. EMBO J. 9, 2351-2359 (1990).
23. A. T. Sasaki, R. A. Firtel, Spatiotemporal regulation of Ras-GTPases during chemotaxis. Methods Mol. Biol. 571, 333-348 (2009).
24. C. Lopez-Alcalá, B. Alvarez-Moya, P. Villalonga, M. Calvo, O. Bachs, N. Agell, Identification of essential interacting elements in K-Ras/calmodulin binding and its role in K-Ras localization. J. Biol. Chem. 283, 10621-10631 (2008).
25. Z. Chen, J. C. Otto, M. O. Bergo, S. G. Young, P. J. Casey, The C-terminal polylysine region and methylation of K-Ras are critical for the interaction between K-Ras and microtubules. J. Biol. Chem. 275, 41251-41257 (2000).
26. B. Boettner, E. E. Govek, J. Cross, L. Van Aelst, The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin. Proc. Natl. Acad. Sci. U.S.A. 97, 9064-9069 (2000).
27. C. D. Hu, K. Kariya, M. Tamada, K. Akasaka, M. Shirouzu, S. Yokoyama, T. Kataoka, Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras. J. Biol. Chem. 270, 30274-30277 (1995).
28. J. K. Drugan, R. Khosravi-Far, M. A. White, C. J. Der, Y. J. Sung, Y. W. Hwang, S. L. Campbell, Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation. J. Biol. Chem. 271, 233-237 (1996).
29. T. R. Brtva, J. K. Drugan, S. Ghosh, R. S. Terrell, S. Campbell-Burk, R. M. Bell, C. J. Der, Two distinct Raf domains mediate interaction with Ras. J. Biol. Chem. 270, 9809-9812 (1995).
30. H. Yan, M. L. Chin, E. A. Horvath, E. A. Kane, C. M. Pfleger, Impairment of ubiquitylation by mutation in Drosophila E1 promotes both cell-autonomous and non-cell-autonomous Ras-ERK activation in vivo. J. Cell Sci. 122, 1461-1470 (2009).
31. H. Yan, M. Jahanshahi, E. A. Horvath, H. Y. Liu, C. M. Pfleger, Rabex-5 ubiquitin ligase activity restricts Ras signaling to establish pathway homeostasis in Drosophila. Curr. Biol. 20, 1378-1382 (2010).
32. Acknowledgments: We gratefully acknowledge the members of the Cantley laboratory and the Izayoi Meeting for stimulating discussions and helpful suggestions; Y.-H. Chiu, Y. Saikawa, F. Okumura, and S. Yoshida for critical comments; X. Yang for help with mass spectrometry experiments and excellent technical assistance; and E. Mullarky and M. Sasaki for help in preparing this manuscript. We thank the Nikon Imaging Center at Harvard Medical School for help with imaging. Funding: A.T.S. was supported, in part, by the Japanese Society for the Promotion of Science Research Fellowship for Research Abroad, Kanae Foundation for Research Abroad, and a Genentech Fellowship. A.C. was supported by a European Molecular Biology Organization Long-Term Fellowship and the Ramón y Cajal Prize. J.W.L. was supported by a fellowship from the American Cancer Society. This work was funded by research grants R01-GM41890, 5P01CA117969 and P01CA089021 to L.C.C. and NIH grants 1P01CA120964-01A1 and 5P30CA006516-43 to J.M.A. Author contributions: A.T.S. designed and performed the experiments and analyzed data; A.C. performed the xenograft assay; J.W.L. performed bioinformatics; E.R.K. and S.H. assisted with the experiments; D.A., K.T., P.P.P., and L.C.C. helped to create the model; and L.C.C. wrote the paper. J.M.A. performed mass spectrometry analysis. Competing interests: The authors declare that they have no competing interests. Data availability: The mass spectrometry data associated with this manuscript may be downloaded from the Proteome Commons Tranche repository at https://proteomecommons.org/tranche/ [Tranche hash: LshL1FF4Fq6DEl0HkO+7ZlTpz05QRx/MpQxJMQK1Uy9n6Qz7HLjROUjlwk/ XlaJBqVQLmQRa0QEpsTU4upcZa8NTXKwAAAAAAAACwA== (Data file 1); XF/Bzb4U/lFXo5cICj2zcwA1M8XYVrWLeOzH8/JMwHFkD52qpYEnrx8tjRiOViNx1s4MIqepYG8Fj/ 0n2V+OxfghtCUAAAAAAAACvw==(Data file 2); 3V2aanplSsrDNjM6rk+MtMelycgeOqTgUMWObZE0hCGKkrCoDMEQ/ XJdCosHUkjgvcBA4nu3Sd1UT42ygyx4PSA8BKEAAAAAAAACvQ== (Data file 3);and 2jU9D8FUZyIBE/ hVj5rK9Rjo0JIOUHL92lnFV6ngXKX9lTRAKQ snAh58fPwZpQhFzJ4ZBB6V1 +BByWwbamtkyB4r2jQAAAAAAAACtQ== (Data file 4)].