CK2 binds, phosphorylates, and regulates its pivotal substrate Cdc37, an Hsp90-cochaperone.
Protein kinase CK2 phosphorylates and regulates a large number of substrates but roles of CK2 in protein kinase-mediated signal transduction systems remain largely uncertain. Cdc37 is a protein kinase-targeting molecular chaperone and its function in cooperation with Hsp90 is required for various signaling kinases. In this article, interaction between CK2 and Cdc37 is described. We present evidence indicating that phosphorylation of Cdc37 by CK2 in conserved Ser13 in the N-terminal extremity was prerequisite for the efficient binding activity of Cdc37 to protein kinases including Akt, Cdk4, MOK, and Raf1. In addition, the phosphorylation of Cdc37 by CK2 was crucial for the recruitment of Hsp90 to the protein kinase-Cdc37 complexes. We observed that a subset of CK2 was associated with Hsp90 and Cdc37 in cells. Whereas Hsp90 and Cdc37 were exclusively distributed in the cytoplasm, CK2alpha and CK2beta were localized mainly in the nucleus but also in the cytoplasm with different patterns. Moreover, direct association of Cdc37 with CK2alpha was observed in an E. coli system. Collectively, these findings indicated that a subpopulation of CK2 forms complexes with Hsp90 and Cdc37 in the cytoplasm and phosphorylates Cdc37, thus regulates the molecular chaperone activity of Cdc37. Since CK2 activity depends on Cdc37, CK2 and Cdc37 constitute a positive feedback machinery to control multiple Cdc37-dependent signaling protein kinases. The structure of Cdc37 and physiological importance of the CK2-Cdc37 interaction are discussed.
Miyata
Yoshihiko
Y
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan. ymiyata@Lif.kyoto-u.ac.jp
Nishida
Eisuke
E
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D004926:Escherichia coli; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D002352:Carrier Proteins; C103269:Cdc37 protein, rat; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D011494:Protein Kinases; D047390:Casein Kinase II