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Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination.

ABSTRACT: Ras proteins play a central role in transducing signals that control cell proliferation, differentiation, motility, and survival. The location-specific signaling activity of Ras has been previously shown to be regulated by ubiquitination [1]. However, the molecular machinery that controls Ras ubiquitination has not been defined. Here we demonstrate through biochemical and functional analyses that Rabex-5 (also known as RabGEF1) [2, 3] functions as an E3 ligase for Ras. Rabex-5-mediated Ras ubiquitination promotes Ras endosomal localization and leads to the suppression of ERK activation. Moreover, the Ras effector RIN1 [4, 5] is required for Rabex-5-dependent Ras ubiquitination, suggesting a feedback mechanism by which Ras activation can be coupled to ubiquitination. These findings define new elements in the regulatory circuitry that link Ras compartmentalization to signaling output.

SUBMITTER: Xu L

PROVIDER: S-EPMC3436604 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination.

Xu Lizhong L Lubkov Veronica V Taylor Laura J LJ Bar-Sagi Dafna D

Current biology : CB 20100722 15

Ras proteins play a central role in transducing signals that control cell proliferation, differentiation, motility, and survival. The location-specific signaling activity of Ras has been previously shown to be regulated by ubiquitination [1]. However, the molecular machinery that controls Ras ubiquitination has not been defined. Here we demonstrate through biochemical and functional analyses that Rabex-5 (also known as RabGEF1) [2, 3] functions as an E3 ligase for Ras. Rabex-5-mediated Ras ubiqu ...[more]

PMID: 20655225

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