A positive feedback loop between protein kinase CKII and Cdc37 promotes the activity of multiple protein kinases.
We report here the identification of CDC37, 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 alpha' 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, only CDC37 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 phosphorylation in 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 and cdc37-S17A mutants at 37 degrees C, and cdc37-S14A or cdc37-S14,17A overexpression was incapable of protecting cka2-13 mutants on media containing geldanamycin. Additionally, CKII activity was elevated in cells arrested at the G(1) and G(2)/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.
Mesh Terms:
Amino Acid Sequence, Casein Kinase II, Cell Cycle Proteins, Drosophila Proteins, Feedback, Genotype, HSP90 Heat-Shock Proteins, Kinetics, Molecular Chaperones, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Protein Kinases, Protein Subunits, Protein-Serine-Threonine Kinases, Recombinant Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Substrate Specificity
Amino Acid Sequence, Casein Kinase II, Cell Cycle Proteins, Drosophila Proteins, Feedback, Genotype, HSP90 Heat-Shock Proteins, Kinetics, Molecular Chaperones, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Protein Kinases, Protein Subunits, Protein-Serine-Threonine Kinases, Recombinant Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Substrate Specificity
J. Biol. Chem.
Date: Jan. 31, 2003
PubMed ID: 12435747
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