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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.

Pubmed ID: 12435747

Authors

  • Bandhakavi S
  • McCann RO
  • Hanna DE
  • Glover CV

Journal

The Journal of biological chemistry

Publication Data

January 31, 2003

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM54626

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