MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch

Young Ho Ahn, Jonathan M. Kurie

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)29399-29404
Number of pages6
JournalJournal of Biological Chemistry
Volume284
Issue number43
DOIs
StatePublished - 23 Oct 2009

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