MKK4/SEK1 Is Negatively Regulated through a Feedback Loop Involving the E3 Ubiquitin Ligase Itch

Cells exposed to environmental stress rapidly activate the MAPK cascade (MKKK/MKK/MAPK). The transient nature of stress signaling is a consequence of negative feedback signals that lead to kinase dephosphorylation, degradation, and sequestration, which have not been fully elucidated for MKK family m...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2009-10, Vol.284 (43), p.29399-29404
Main Authors: Ahn, Young-Ho, Kurie, Jonathan M.
Format: Article
Language:English
Subjects:
Animals
CHO Cells
Cricetinae
Cricetulus
Humans
MAP Kinase Kinase 4 - genetics
MAP Kinase Kinase 4 - metabolism
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Mechanisms of Signal Transduction
Proteasome Endopeptidase Complex - genetics
Proteasome Endopeptidase Complex - metabolism
Sorbitol - pharmacology
Sweetening Agents - pharmacology
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination - drug effects
Ubiquitination - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cells exposed to environmental stress rapidly activate the MAPK cascade (MKKK/MKK/MAPK). The transient nature of stress signaling is a consequence of negative feedback signals that lead to kinase dephosphorylation, degradation, and sequestration, which have not been fully elucidated for MKK family members. Here, we investigated the signals that negatively regulate MKK4/SEK1, an upstream activator of the MAPKs JNK and p38/HOG1. Following exposure of cells to sorbitol, MKK4 underwent ubiquitination and degradation in a proteasome-dependent manner. MKK4 ubiquitination required JNK kinase activity. The JNK substrate Itch (a HECT domain-containing Nedd4-like ubiquitin protein ligase) bound to MKK4, ubiquitinated lysines 140 and 143, and promoted MKK4 degradation. Other E3 ligases within the MAPK modular complex did not ubiquitinate MKK4. These data suggest that MKK4 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase Itch, which has a fundamental role in the mechanism that controls MKK4 protein levels.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.044958