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HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold.


ABSTRACT: Scaffold proteins play a critical role in controlling the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Shoc2 is a leucine-rich repeat scaffold protein that acts as a positive modulator of ERK1/2 signaling. However, the precise mechanism by which Shoc2 modulates the activity of the ERK1/2 pathway is unclear. Here we report the identification of the E3 ubiquitin ligase HUWE1 as a binding partner and regulator of Shoc2 function. HUWE1 mediates ubiquitination and, consequently, the levels of Shoc2. Additionally, we show that both Shoc2 and HUWE1 are necessary to control the levels and ubiquitination of the Shoc2 signaling partner, RAF-1. Depletion of HUWE1 abolishes RAF-1 ubiquitination, with corresponding changes in ERK1/2 pathway activity occurring. Our results indicate that the HUWE1-mediated ubiquitination of Shoc2 is the switch that regulates the transition from an active to an inactive state of the RAF-1 kinase. Taken together, our results demonstrate that HUWE1 is a novel player involved in regulating ERK1/2 signal transmission through the Shoc2 scaffold complex.

SUBMITTER: Jang ER 

PROVIDER: S-EPMC4187736 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold.

Jang Eun Ryoung ER   Shi Ping P   Bryant Jamal J   Chen Jing J   Dukhande Vikas V   Gentry Matthew S MS   Jang HyeIn H   Jeoung Myoungkun M   Galperin Emilia E  

Molecular and cellular biology 20140714 19


Scaffold proteins play a critical role in controlling the activity of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Shoc2 is a leucine-rich repeat scaffold protein that acts as a positive modulator of ERK1/2 signaling. However, the precise mechanism by which Shoc2 modulates the activity of the ERK1/2 pathway is unclear. Here we report the identification of the E3 ubiquitin ligase HUWE1 as a binding partner and regulator of Shoc2 function. HUWE1 mediates ubiquitination and, cons  ...[more]

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