CK2 Controls Multiple Protein Kinases by Phosphorylating a Kinase-Targeting Molecular Chaperone, Cdc37

Abstract

Cdc37 is a kinase-associated molecular chaperone whose function in concert with Hsp90 is essential for many signaling protein kinases. Here, we report that mammalian Cdc37 is a pivotal substrate of CK2 (casein kinase II). Purified Cdc37 was phosphorylated in vitro on a conserved serine residue, Ser13, by CK2. Moreover, Ser13 was the unique phosphorylation site of Cdc37 in vivo. Crucially, the CK2 phosphorylation of Cdc37 on Ser13 was essential for the optimal binding activity of Cdc37 toward various kinases examined, including Raf1, Akt, Aurora-B, Cdk4, Src, MOK, MAK, and MRK. In addition, nonphosphorylatable mutants of Cdc37 significantly suppressed the association of Hsp90 with protein kinases, while the Hsp90-binding activity of the mutants was unchanged. The treatment of cells with a specific CK2 inhibitor suppressed the phosphorylation of Cdc37 in vivo and reduced the levels of Cdc37 target kinases. These results unveil a regulatory mechanism of Cdc37, identify a novel molecular link between CK2 and many crucial protein kinases via Cdc37, and reveal the molecular basis for the ability of CK2 to regulate pleiotropic cellular functions.

We thank T. Aoki and M. Nakagawa for excellent technical assistance, L. A. Pinna and F. Meggio for providing CK2 inhibitor TBB, M. MacLean and D. Picard (Université de Genève) for sending us an excellent review on Cdc37 before publication, Y. Kimura (Tokyo Metropolitan Institute of Medical Science) for discussion and suggestion, and F. Toyoshima (Kyoto University), C. Sherr (Howard Hughes Medical Institute and St. Jude Children's Research Hospital), M. Shibuya (University of Tokyo), Y. Ikawa (Tokyo Medical and Dental University/RIKEN), S. Hattori (University of Tokyo), and H. Sabe (Osaka Bioscience Institute) for cDNA of Aurora-B, Cdk4, MAK, MRK, Raf1, and v-Src, respectively.

This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.