The PHD Domain of MEKK1 Acts as an E3 Ubiquitin Ligase and Mediates Ubiquitination and Degradation of ERK1/2
- 1 May 2002
- journal article
- research article
- Published by Elsevier BV in Molecular Cell
- Vol. 9 (5), 945-956
- https://doi.org/10.1016/s1097-2765(02)00519-1
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.Keywords
Funding Information
- U.S. Public Health Service (CA14195, CA82863, 6FB-0108, GM 56498)
- California Breast Cancer Research Program (CA14195, CA82863, 6FB-0108, GM 56498)
- National Institutes of Health (CA14195, CA82863, 6FB-0108, GM 56498)
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