CK2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, Cdc37.
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.
Miyata
Yoshihiko
Y
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan. ymiyata@Lif.kyoto-u.ac.jp
Nishida
Eisuke
E
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins; D047390:Casein Kinase II; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine
C498362:CDC37 protein, human; D002352:Carrier Proteins; C103269:Cdc37 protein, rat; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018832:Molecular Chaperones; D012694:Serine; D011494:Protein Kinases; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D018833:Chaperonins