The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2

Zhimin Lu, Shuichan Xu, Claudio Joazeiro, Melanie H. Cobb, Tony Hunter

Research output: Contribution to journalArticle

251 Citations (Scopus)

Abstract

ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Moreover, both MEKK1 kinase activity and the docking motif on ERK1/2 were involved in ERK1/2 ubiquitination. Significantly, cells expressing ERK2 with the docking motif mutation were resistant to sorbitol-induced apoptosis. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity.

Original languageEnglish (US)
Pages (from-to)945-956
Number of pages12
JournalMolecular Cell
Volume9
Issue number5
DOIs
StatePublished - 2002

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Ubiquitin-Protein Ligases
Ubiquitination
Phosphotransferases
Sorbitol
Mitogen-Activated Protein Kinase 1
Proteasome Endopeptidase Complex
Threonine
Ubiquitin
Tyrosine
Down-Regulation
Phosphorylation
Apoptosis
Mutation
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology

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The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. / Lu, Zhimin; Xu, Shuichan; Joazeiro, Claudio; Cobb, Melanie H.; Hunter, Tony.

In: Molecular Cell, Vol. 9, No. 5, 2002, p. 945-956.

Research output: Contribution to journalArticle

Lu, Zhimin ; Xu, Shuichan ; Joazeiro, Claudio ; Cobb, Melanie H. ; Hunter, Tony. / The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. In: Molecular Cell. 2002 ; Vol. 9, No. 5. pp. 945-956.
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