Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4.
CDC37, an essential gene in Saccharomyces cerevisiae, interacts genetically with multiple protein kinases and is required for production of Cdc28p/cyclin complexes through an unknown mechanism. We have identified mammalian p50Cdc37 as a protein kinase-targeting subunit of the molecular chaperone Hsp90. Previously, p50 was observed in complexes with pp60v-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 through G1. In insect cells, Cdc37 is sufficient to target Hsp90 to Cdk4 and both in vitro and in vivo, Cdc37/Hsp90 associates preferentially with the fraction of Cdk4 not bound to D-type cyclins. Cdc37 is coexpressed with cyclin Dl in cells undergoing programmed proliferation in vivo, consistent with a positive role in cell cycle progression. Pharmacological inactivation of Cdc37/Hsp90 function decreases the half-life of newly synthesized Cdk4, indicating a role for Cdc37/Hsp90 in Cdk4 stabilization. This study suggests a general role for p50Cdc37 in signaling pathways dependent on intrinsically unstable protein kinases and reveals a previously unrecognized chaperone-dependent step in the production of Cdk4/cyclin D complexes.
Pubmed ID: 8666233 RIS Download
Amino Acid Sequence | Animals | Base Sequence | Cell Cycle Proteins | Chaperonins | Cloning, Molecular | Cyclin D | Cyclin-Dependent Kinase 4 | Cyclin-Dependent Kinases | Cyclins | Cytoplasm | Drosophila Proteins | Enzyme Stability | Fibroblasts | Gene Expression Regulation | HSP90 Heat-Shock Proteins | Humans | Mice | Molecular Chaperones | Molecular Sequence Data | Molecular Weight | Proto-Oncogene Proteins | Saccharomyces cerevisiae Proteins | Sequence Homology, Amino Acid