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J Biol Chem

Title:		Dynamic ubiquitination of the mitogen-activated protein kinase kinase (MAPKK) Ste7 determines mitogen-activated protein kinase (MAPK) specificity
Author(s):		Hurst JH; Dohlman HG;
Address:		"Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA"
Journal Title:		J Biol Chem
Year:		2013
Volume:		20130503
Issue:		26
Page Number:		18660 - 18671
DOI:		10.1074/jbc.M113.475707
ISSN/ISBN:		1083-351X (Electronic) 0021-9258 (Print) 0021-9258 (Linking)
Abstract:		"Ubiquitination is a post-translational modification that tags proteins for proteasomal degradation. In addition, there is a growing appreciation that ubiquitination can influence protein activity and localization. Ste7 is a prototype MAPKK in yeast that participates in both the pheromone signaling and nutrient deprivation/invasive growth pathways. We have shown previously that Ste7 is ubiquitinated upon pheromone stimulation. Here, we show that the Skp1/Cullin/F-box ubiquitin ligase SCF(Cdc4) and the ubiquitin protease Ubp3 regulate Ste7 ubiquitination and signal specificity. Using purified components, we demonstrate that SCF(Cdc4) ubiquitinates Ste7 directly. Using gene deletion mutants, we show that SCF(Cdc4) and Ubp3 have opposing effects on Ste7 ubiquitination. Although SCF(Cdc4) is necessary for proper activation of the pheromone MAPK Fus3, Ubp3 is needed to limit activation of the invasive growth MAPK Kss1. Finally, we show that Fus3 phosphorylates Ubp3 directly and that phosphorylation of Ubp3 is necessary to limit Kss1 activation. These results reveal a feedback loop wherein one MAPK limits the ubiquitination of an upstream MAPKK and thereby prevents spurious activation of a second competing MAPK"
Keywords:		"Cell Cycle Proteins/metabolism Endopeptidases/metabolism Enzyme Activation F-Box Proteins/metabolism Gene Deletion *Gene Expression Regulation, Fungal Mitogen-Activated Protein Kinase Kinases/*metabolism Mitogen-Activated Protein Kinases/metabolism Mutati;"
Notes:		"MedlineHurst, Jillian H Dohlman, Henrik G eng F32 GM096597/GM/NIGMS NIH HHS/ R01 GM059167/GM/NIGMS NIH HHS/ GM096597/GM/NIGMS NIH HHS/ R01-GM059167/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural 2013/05/07 J Biol Chem. 2013 Jun 28; 288(26):18660-71. doi: 10.1074/jbc.M113.475707. Epub 2013 May 3"