Supervision of multiple signaling protein kinases by the CK2-Cdc37 couple, a possible novel cancer therapeutic target.
Overexpression of a pleiotropic Ser/Thr kinase CK2 (casein kinase II), or of a kinase-targeting molecular chaperone Cdc37, induces neoplastic cell growth in animals. Recent genetic and biochemical evidence from several laboratories has revealed an unexpected direct link between CK2 and Cdc37. In this short review, we describe the basic characteristics of CK2 and Cdc37 and introduce recent findings on the interaction between CK2 and Cdc37. Cdc37 was identified as a multicopy suppressor of a temperature-sensitive allele of CK2 in Saccharomyces cerevisiae. CK2 phosphorylates a conserved serine residue in the N-terminal extremity of Cdc37 in vitro and in yeast as well as mammalian cells, and this is the unique phosphorylation site of Cdc37 under normal conditions. Mutations in the CK2-mediated phosphorylation site abolish the association of Cdc37 with various protein kinases. The same mutations in yeast cause severe growth and morphological defects. Specific inhibition of CK2 activity decreases intracellular levels of Cdc37-dependent protein kinases. Altogether, this evidence clearly indicates that the CK2-dependent phosphorylation is essential for the proper function of Cdc37 to bind and stabilize signaling protein kinases. In contrast, CK2 activity is enhanced by Cdc37 both in vitro and in vivo; thus, the CK2-Cdc37 couple seems to constitute a positive feedback control mechanism that may govern the activity of multiple protein kinases. Cdc37-dependent protein kinases include important signaling molecules whose disregulations are intimately related to neoplastic cell growth; hence, inhibition of the CK2-Cdc37 system may simultaneously suppress various cancer-promoting signal cascades. We propose that the CK2-Cdc37 couple can be a novel and efficient pharmacological target for cancer chemotherapy.
Miyata
Yoshihiko
Y
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. ymiyata@lif.kyoto-u.ac.jp
Nishida
Eisuke
E
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D000970:Antineoplastic Agents; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D011494:Protein Kinases; D018833:Chaperonins