Research ArticleCell Biology

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

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Science Signaling  08 Mar 2011:
Vol. 4, Issue 163, pp. ra13
DOI: 10.1126/scisignal.2001518

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Ubiquitination for Activity

Mutational activation of the guanosine triphosphatase (GTPase) Ras occurs frequently in various cancers. Although the three mammalian isoforms—N-Ras, H-Ras, and K-Ras—couple to the same set of downstream signaling pathways, mutations in each isoform are associated with different types of cancers. In contrast to previous work showing that ubiquitination of N-Ras and H-Ras restricts their activity, Sasaki et al. found that monoubiquitination of Lys147 in K-Ras increased its activity and its ability to bind to downstream effector proteins. Cells expressing the oncogenic G12V mutant of Ras form tumors when injected into mice; however, cells expressing G12V Ras with an additional mutation abolishing ubiquitination of Lys147 formed smaller tumors in mice. Thus, cancers in which K-Ras activation drives tumor growth and survival could be targeted by treatments blocking K-Ras ubiquitination. The accompanying Perspective by Pfleger provides context on the distinct effects of ubiquitination on the abundance, activity, and access to effectors of different Ras isoforms.