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J. Biol. Chem., Vol. 280, Issue 24, 22679-22687, June 17, 2005

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The Sphingoid Long Chain Base Phytosphingosine Activates AGC-type Protein Kinases in Saccharomyces cerevisiae Including Ypk1, Ypk2, and Sch9^*

Ke Liu, Xiping Zhang, Robert L. Lester, and Robert C. Dickson

From the Department of Molecular and Cellular Biochemistry and the Lucille P. Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536

The Pkh1 protein kinase of Saccharomyces cerevisiae, a homolog of the mammalian 3-phosphoinositide-dependent kinase (PDK1), regulates downstream AGC-type protein kinases including Ypk1/2 and Pkc1, which control cell wall integrity, growth, and other processes. Phytosphingosine (PHS), a sphingoid long chain base, is hypothesized to be a lipid activator of Pkh1 and thereby controls the activity of Ypk1/2. Here we present biochemical evidence supporting this hypothesis, and in addition we demonstrate that PHS also stimulates autophosphorylation and activation of Ypk1/2. Greatest stimulation of Ypk1/2 phosphorylation and activity are achieved by inclusion of both PHS and Pkh1 in an in vitro kinase reaction. We also demonstrate for the first time that Pkh1 phosphorylates the Sch9 protein kinase in vitro and that such phosphorylation is stimulated by PHS. This is the first biochemical demonstration of Sch9 activators, and the results further support roles for long chain bases in heat stress resistance in addition to implying roles in chronological aging and cell size determination, since Sch9 functions in these processes. Thus, our data support a model in which PHS, rather than simply being an upstream activator of Pkh1, also activates kinases that are downstream targets of Pkh1 including Ypk1/2 and Sch9.

Received for publication, March 17, 2005 , and in revised form, April 15, 2005.

^* This work was supported by National Institutes of Health Grants GM 41302 and AG 024377 (to R. C. D.) and by COBRA Grant P20 RR020171 (to Louis Hersh). 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.

To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 800 Rose St., Lexington, KY 40536. Tel.: 859-323-6052; Fax: 859-257-8940; E-mail: bobd{at}uky.edu.

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