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J. Biol. Chem., Vol. 278, Issue 32, 30074-30082, August 8, 2003

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The Kelch Repeat Protein, Tea1, Is a Potential Substrate Target of the p21-activated Kinase, Shk1, in the Fission Yeast, Schizosaccharomyces pombe^*

HyeWon Kim  , Peirong Yang  , Paola Catanuto ¶, Fulvia Verde ¶, Hong Lai , Hongyan Du , Fred Chang || and Stevan Marcus  **

From the Department of Molecular Genetics and Program in Genes and Development, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, the ^¶Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida 33136-1015, and the ^||Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 10032

The p21-activated kinase (PAK) homolog, Shk1, is a critical component of a multifunctional Ras/Cdc42/PAK complex required for viability, polarized growth and cell shape, and sexual differentiation in the fission yeast, Schizosaccharomyces pombe. Substrate targets of the Shk1 kinase have not previously been described. Here we show that the S. pombe cell polarity factor, Tea1, is directly phosphorylated by Shk1 in vitro. We demonstrate further that Tea1 is phosphorylated in S. pombe cells and that its level of phosphorylation is significantly reduced in cells defective in Shk1 function. Consistent with a role for Tea1 as a potential downstream effector of Shk1, we show that a tea1 null mutation rescues the Shk1 hyperactivity-induced lethal phenotype caused by loss of function of the essential Shk1 inhibitor, Skb15. All phenotypes associated with Skb15 loss, including defects in actin cytoskeletal organization, chromosome segregation, and cytokinesis, are suppressed by tea1, suggesting that Tea1 is a potential mediator of multiple Shk1 functions. S. pombe cells carrying a weak hypomorphic allele of shk1 together with a tea1 mutation exhibit a cytokinesis defective phenotype that is significantly more severe than that observed in the respective single mutants, providing evidence that Shk1 and Tea1 cooperate to regulate cytokinesis. In addition, we show that S. pombe cells carrying the orb2-34 allele of shk1 exhibit a pattern of monopolar growth similar to that observed in tea1 cells, suggesting that Shk1 and Tea1 may regulate one or more common processes involved in the regulation of polarized cell growth. Taken together, our results strongly implicate Tea1 as a potential substrate-effector of the Shk1 kinase.

Received for publication, March 14, 2003 , and in revised form, April 25, 2003.

^* This study was supported by National Institutes of Health Grants R01GM53239 (to S. M.) and R01GM56836 (to F. C.), a project support grant from the University of Texas M. D. Anderson Center (to S. M.), a Nikon Fellowship at the Marine Biological Laboratories (to F. C.), American Cancer Society Research Project Grant RPG-00-044-01-CCG (to F. V.), Human Frontier Science Program Grant RG0295 (to F. V.), and the University of Miami Sylvester Cancer Center (to F. V.). 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.

These authors contributed equally to this work and are listed alphabetically.

^** To whom correspondence should be addressed. Tel.: 713-745-2032; Fax: 713-794-4394; E-mail:smarcus{at}mdacc.tmc.edu.

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