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

GTP-loaded Ras induces multiple signaling pathways by binding to its numerous effectors such as Raf and PI3K. Ras activity can be influenced by activation of Ras-GEFs that stimulate GDP release and GTP loading or by inhibition of Ras-GAPs that stimulate GTP hydrolysis. Here, we report that monoubiqu...

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Published in:Science signaling 2011-03, Vol.4 (163), p.ra13-ra13
Main Authors: Sasaki, Atsuo T., Carracedo, Arkaitz, Locasale, Jason W., Anastasiou, Dimitrios, Takeuchi, Koh, Kahoud, Emily Rose, Haviv, Sasson, Asara, John M., Pandolfi, Pier Paolo, Cantley, Lewis C.
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Language:English
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Summary:GTP-loaded Ras induces multiple signaling pathways by binding to its numerous effectors such as Raf and PI3K. Ras activity can be influenced by activation of Ras-GEFs that stimulate GDP release and GTP loading or by inhibition of Ras-GAPs that stimulate GTP hydrolysis. Here, we report that monoubiquitination of Lys 147 within the G domain of wild-type K-Ras, the Ras gene most frequently mutated in cancer, leads to enhanced GTP loading. Furthermore, ubiquitination increases the ability of the oncogenic Gly-12-Val mutant of K-Ras to bind the downstream effectors PI3K and Raf. These results indicate that monoubiquitination both enhances GTP loading on K-Ras and increases its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation.
ISSN:1937-9145
DOI:10.1126/scisignal.2001518