Sci. STKE, 24 June 2003
MAPKS Degrading ERK3
Coulombe et al. discovered that, unlike other mitogen-activated protein kinases (MAPK), regulation of extracellular signal-regulated kinase 3 (ERK3) activity depended on the rate of protein degradation. The activity of MAPKs is primarily regulated through changes in subcellular localization and phosphorylation state. Coulombe et al. attempted to express ERK3, a MAPK whose mRNA levels are regulated during development, in various cell types and discovered that, in contrast to other MAPKs, its protein was undetectable in cell lysates by Western analysis. The authors measured ERK3 stability by Western analysis of ERK3 in immunoprecipitates obtained at various times after pharmacological inhibition of protein synthesis and demonstrated that both endogenous and transfected ERK3 were highly unstable. Pharmacological analysis indicated that the ongoing degradation of ERK3 depended on ubiquitination and proteolysis by the 26S proteasome. Analysis of ERK1-ERK3 chimeric proteins identified two degradation regions in the ERK3 N-terminal lobe; insertion of this lobe into a stable protein confirmed that it functioned as a transferable degradation signal. In two models of cell differentiation (PC12 cells exposed to nerve growth factor and a line of myogenic cells grown in low serum), differentiation was accompanied by a rise in ERK3. In the myogenic cells, this increase in ERK3 largely depended on increased protein stability. In 3T3 fibroblasts, moreover, expression of a stabilized ERK3 mutant inhibited cell-cycle progression. These data suggest that, unlike other MAPKs, the activity of ERK3 is largely regulated through control of protein degradation.
P. Coulombe, G. Rodier, S. Pelletier, J. Pellerin, S. Meloches, Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-associated protein kinase regulation during cellular differentiation. Mol. Cell. Biol. 23, 4542-4558 (2003). [Abstract] [Full Text]
Citation: Degrading ERK3. Sci. STKE 2003, tw241 (2003).
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