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J. Biol. Chem., Vol. 283, Issue 4, 1954-1961, January 25, 2008

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Down-regulation of Pkc1-mediated Signaling by the Deubiquitinating Enzyme Ubp3^*

From the Department of Biology, Saint Louis University, St. Louis, Missouri 63103

Regulated ubiquitination and degradation of signaling proteins have emerged as key mechanisms for modulating the strength and duration of signaling pathways. The reversible nature of the ubiquitination process as well as the large number and diversity of the deubiquitinating enzymes raise the possibility that signaling pathways might be modulated by specific deubiquitinating enzyme(s). Here we provide evidence that in the yeast Saccharomyces cerevisiae, the Pkc1-mediated signaling pathway that controls the cell wall integrity is negatively regulated by the deubiquitinating enzyme Ubp3. Disruption of the UBP3 gene leads to an enhanced activation of the cell wall integrity pathway MAPK Slt2 when cells are challenged with a variety of pathway activation agents such as pheromone and Congo red. The ubp3 deletion mutants accumulate high levels of Pkc1, suggesting potential regulation of Pkc1 by Ubp3. Consistent with this, Pkc1 and Ubp3 interact in vivo, and the stability of Pkc1 is markedly increased in the ubp3 deletion mutants. Moreover, disruption of the PKC1 gene, but not the genes that encode components downstream of Pkc1, completely suppresses other phenotypes displayed by the ubp3 deletion mutants such as hyperactivation of the pheromone-responsive MAPK Fus3 (Wang, Y., and Dohlman, H. G. (2002) J. Biol. Chem. 277, 15766–15772). These findings demonstrate that Ubp3 can regulate Pkc1 by facilitating its destruction and provide the initial evidence that Pkc1 plays a positive role in modulating the parallel pheromone-signaling pathway.

Received for publication, July 11, 2007 , and in revised form, November 5, 2007.

^* This work was supported by American Heart Association Scientist Development Grant 0635271N, a Saint Louis University Beaumont Faculty Development Award, and a summer research award (to Y. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biology, Saint Louis University, 128 Macelwane Hall, 3507 Laclede Ave., St. Louis, MO 63103. Tel.: 314-977-4178; Fax: 314-977-3658; E-mail: ywang8{at}slu.edu.

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