MAMMALIAN P50(CDC37) IS A PROTEIN KINASE-TARGETING SUBUNIT OF HSP90 THAT BINDS AND STABILIZES CDK4

CDC37, an essential gene in Saccharomyces cerevisiae, interacts geneti cally with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identifi ed mammalian p50(Cdc37) as a protein kinase-targeting subunit of the m olecular chaperone Hsp90. Previously, p50 was observed in complexes wi th pp60(v-src) and Raf-1, but its identity and function have remained elusive. In mouse fibroblasts, a primary target of Cdc37 is Cdk4. This kinase is activated by D-type cyclins and functions in passage throug h G(1). In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 a nd both in vitro and in vivo, Cdc37/Hsp90 associates preferentially wi th the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpres sed with cyclin D1 in cells undergoing programmed proliferation in viv o consistent with a positive role in cell cycle progression. Pharmacol ogical inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 sta bilization. This study suggests a general role for p50(Cdc37) in signa ling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the prod uction of Cdk4/cyclin D complexes.