Jang ER, Shi P, Bryant J, Chen J, Dukhante V, Gentry MS, Jang H, Jeoung M, Galperin E

Scaffold proteins play a critical role in controlling the activity of the extracellular signal-regulated kinases (ERK1/2) pathway. Shoc2 is a leucine-rich repeats scaffold protein that acts as a positive modulator of ERK1/2 signaling. However, the precise mechanism by which Shoc2 modulates activity of the ERK1/2 pathway is unclear. Here we ...

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report the identification of the E3 ubiquitin ligase HUWE1 as a binding partner and regulator of Shoc2 function. HUWE1 mediates ubiquitination and consequently 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. Our results indicate that the HUWE1-mediated ubiquitination of Shoc2 is the switch that regulates 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.

Date: Jul. 14, 2014

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