HUWE1 is a Molecular Link Controlling RAF-1 Activity Supported by the Shoc2 Scaffold

Authors

Eun Ryoung Jang, University of KentuckyFollow
Ping Shi, University of Kentucky
Jamal Bryant, University of Kentucky
Jing Chen, University of KentuckyFollow
Vikas Dukhande, University of Kentucky
Matthew S. Gentry, University of KentuckyFollow
HyeIn Jang, University of KentuckyFollow
Myoungkun Jeoung, University of KentuckyFollow
Emilia Galperin, University of KentuckyFollow

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.

Document Type

Article

Publication Date

10-2014

Notes/Citation Information

Published in Molecular and Cellular Biology, v. 34, no. 19, p. 3579-3593.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The copyright holders have granted the permission for posting the article here.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1128/MCB.00811-14

Funding Information

The cores mentioned above are supported in part by a grant from the National Institute of General Medical Sciences (P20GM103486). This project was supported in part by grants from the National Cancer Institute (R00CA126161 to E.G.), the National Institute of General Medical Sciences (P20GM103486), and the National Institute of Neurological Disorders and Stroke (R01NS070899 to M.S.G.) and by an American Heart Association postdoctoral award (12POST12030381 to V.D.).

Repository Citation

Jang, Eun Ryoung; Shi, Ping; Bryant, Jamal; Chen, Jing; Dukhande, Vikas; Gentry, Matthew S.; Jang, HyeIn; Jeoung, Myoungkun; and Galperin, Emilia, "HUWE1 is a Molecular Link Controlling RAF-1 Activity Supported by the Shoc2 Scaffold" (2014). Molecular and Cellular Biochemistry Faculty Publications. 65.
https://uknowledge.uky.edu/biochem_facpub/65