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Sci. Signal., 8 March 2011
Vol. 4, Issue 163, p. ra13
[DOI: 10.1126/scisignal.2001518]

RESEARCH ARTICLES

Ubiquitination of K-Ras Enhances Activation and Facilitates Binding to Select Downstream Effectors

Atsuo T. Sasaki1,2, Arkaitz Carracedo3,4, Jason W. Locasale1,2, Dimitrios Anastasiou1,2, Koh Takeuchi5,6, Emily Rose Kahoud1, Sasson Haviv1, John M. Asara1,7, Pier Paolo Pandolfi3, and Lewis C. Cantley1,2*

1 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
3 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
4 CIC bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
6 Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, 2-3-26 Aomi, Koto, Tokyo 135-0064, Japan.
7 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Abstract: The guanosine triphosphate (GTP)–loaded form of the guanosine triphosphatase (GTPase) Ras initiates multiple signaling pathways by binding to various effectors, such as the kinase Raf and phosphatidylinositol 3-kinase (PI3K). Ras activity is increased by guanine nucleotide exchange factors that stimulate guanosine diphosphate release and GTP loading and is inhibited by GTPase-activating proteins that stimulate GTP hydrolysis. KRAS is the most frequently mutated RAS gene in cancer. Here, we report that monoubiquitination of lysine-147 in the guanine nucleotide–binding motif of wild-type K-Ras could lead to enhanced GTP loading. Furthermore, ubiquitination increased the binding of the oncogenic Gly12Val mutant of K-Ras to the downstream effectors PI3K and Raf. Thus, monoubiquitination could enhance GTP loading on K-Ras and increase its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation.

* To whom correspondence should be addressed. E-mail: lcantley{at}hms.harvard.edu

Citation: A. T. Sasaki, A. Carracedo, J. W. Locasale, D. Anastasiou, K. Takeuchi, E. R. Kahoud, S. Haviv, J. M. Asara, P. P. Pandolfi, L. C. Cantley, Ubiquitination of K-Ras Enhances Activation and Facilitates Binding to Select Downstream Effectors. Sci. Signal. 4, ra13 (2011).

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