1. HUWE1 Is a Molecular Link Controlling RAF-1 Activity Supported by the Shoc2 Scaffold
- Author
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HyeIn Jang, Emilia Galperin, Jing Chen, Jamal Bryant, Matthew S. Gentry, Ping Shi, Eun Ryoung Jang, Vikas V. Dukhande, and Myoungkun Jeoung
- Subjects
Models, Molecular ,Scaffold protein ,Ubiquitin-Protein Ligases ,Regulator ,Ubiquitin ,Chlorocebus aethiops ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Molecular Biology ,biology ,Kinase ,Tumor Suppressor Proteins ,HEK 293 cells ,Intracellular Signaling Peptides and Proteins ,Ubiquitination ,Articles ,Cell Biology ,Cell biology ,Ubiquitin ligase ,Proto-Oncogene Proteins c-raf ,HEK293 Cells ,Gene Expression Regulation ,COS Cells ,biology.protein ,Signal transduction ,HeLa Cells ,Signal Transduction - 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.
- Published
- 2014