Journal of Biological Chemistry
Volume 278, Issue 5, 31 January 2003, Pages 2829-2836
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MECHANISMS OF SIGNAL TRANSDUCTION
A Positive Feedback Loop between Protein Kinase CKII and Cdc37 Promotes the Activity of Multiple Protein Kinases*

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We report here the identification ofCDC37, which encodes a putative Hsp90 co-chaperone, as a multicopy suppressor of a temperature-sensitive allele (cka2-13 ts) of the CKA2 gene encoding the α′ catalytic subunit of protein kinase CKII. Unlike wild-type cells, cka2-13 cells were sensitive to the Hsp90-specific inhibitor geldanamycin, and this sensitivity was suppressed by overexpression of either Hsp90 or Cdc37. However, onlyCDC37 was capable of suppressing the temperature sensitivity of a cka2-13 strain, implying that Cdc37 is the limiting component. Immunoprecipitation of metabolically labeled Cdc37 from wild-type versus cka2-13 strains revealed that Cdc37 is a physiological substrate of CKII, and Ser-14 and/or Ser-17 were identified as the most likely sites of CKII phosphorylationin vivo. A cdc37-S14,17A strain lacking these phosphorylation sites exhibited severe growth and morphological defects that were partially reversed in a cdc37-S14,17E strain. Reduced CKII activity was observed in both cdc37-S14A andcdc37-S17A mutants at 37 °C, and cdc37-S14Aor cdc37-S14,17A overexpression was incapable of protectingcka2-13 mutants on media containing geldanamycin. Additionally, CKII activity was elevated in cells arrested at the G1 and G2/M phases of the cell cycle, the same phases during which Cdc37 function is essential. Collectively, these data define a positive feedback loop between CKII and Cdc37. Additional genetic assays demonstrate that this CKII/Cdc37 interaction positively regulates the activity of multiple protein kinases in addition to CKII.

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Published, JBC Papers in Press, November 14, 2002, DOI 10.1074/jbc.M206662200

*

This work was supported by National Institutes of Health Grant GM54626 (to C. V. C. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The first and second authors contributed equally to this work.

§

Present address: Dept. of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208.

Present address: Dept. of Biochemistry, University of Kentucky, Lexington, KY 40506.