Differential Regulation of G1 CDK Complexes by the Hsp90-Cdc37 Chaperone System

Cell Rep. 2017 Oct 31;21(5):1386-1398. doi: 10.1016/j.celrep.2017.10.042.

Abstract

Selective recruitment of protein kinases to the Hsp90 system is mediated by the adaptor co-chaperone Cdc37. We show that assembly of CDK4 and CDK6 into protein complexes is differentially regulated by the Cdc37-Hsp90 system. Like other Hsp90 kinase clients, binding of CDK4/6 to Cdc37 is blocked by ATP-competitive inhibitors. Cdc37-Hsp90 relinquishes CDK6 to D3- and virus-type cyclins and to INK family CDK inhibitors, whereas CDK4 is relinquished to INKs but less readily to cyclins. p21CIP1 and p27KIP1 CDK inhibitors are less potent than the INKs at displacing CDK4 and CDK6 from Cdc37. However, they cooperate with the D-type cyclins to generate CDK4/6-containing ternary complexes that are resistant to cyclin D displacement by Cdc37, suggesting a molecular mechanism to explain the assembly factor activity ascribed to CIP/KIP family members. Overall, our data reveal multiple mechanisms whereby the Hsp90 system may control formation of CDK4- and CDK6-cyclin complexes under different cellular conditions.

Keywords: CDK; CIP/KIP; Cdc37; Hsp90; INK; chaperone; cyclin D; kinase; palbociclib; ribociclib.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Aminopyridines / chemistry
  • Aminopyridines / metabolism
  • Benzimidazoles / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Chaperonins / antagonists & inhibitors
  • Chaperonins / genetics
  • Chaperonins / metabolism*
  • Cyclin D / metabolism
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / metabolism*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Fluorescence Resonance Energy Transfer
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Protein Binding
  • Purines / chemistry
  • Purines / metabolism
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Surface Plasmon Resonance

Substances

  • Aminopyridines
  • Benzimidazoles
  • CDC37 protein, human
  • Cell Cycle Proteins
  • Cyclin D
  • Cyclin-Dependent Kinase Inhibitor p16
  • HSP90 Heat-Shock Proteins
  • Piperazines
  • Purines
  • Pyridines
  • Cyclin-Dependent Kinase Inhibitor p27
  • abemaciclib
  • Adenosine Triphosphate
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Chaperonins
  • palbociclib
  • ribociclib