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Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors

Mark R Woodford1, Andrew W Truman2, Diana M Dunn1

  • 1Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.

Cell Reports
|January 26, 2016
PubMed

Insights

The mitotic checkpoint kinase Mps1 regulates Hsp90 chaperone activity through phosphorylation, impacting tumor cell survival and sensitivity to Hsp90 inhibitors. Mps1 levels may predict patient response to these cancer drugs.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • The molecular chaperone Hsp90 is crucial for tumor growth and survival by stabilizing deregulated signaling proteins.
  • Tumors exhibit sensitivity and selectivity towards Hsp90 inhibitors, but the underlying molecular mechanisms are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which Hsp90 function is regulated in cancer.
  • To investigate the role of Mps1 in Hsp90 regulation and its implications for Hsp90 inhibitor efficacy.

Main Methods:

  • Investigated the phosphorylation of Hsp90 by Mps1 using biochemical assays.
  • Analyzed the effect of Hsp90 phosphorylation on its ATPase activity and client interactions.
  • Identified the phosphatase responsible for Hsp90 dephosphorylation and its impact on Mps1 stability.
  • Correlated Mps1 expression levels with tumor response to Hsp90 inhibitors in renal cell carcinoma models.

Main Results:

  • Mps1 phosphorylates Hsp90 at a conserved threonine residue, reducing its ATPase activity and promoting association with kinase clients like Mps1.
  • Hsp90 phosphorylation is essential for mitotic checkpoint function by stabilizing Mps1.
  • Cdc14 phosphatase dephosphorylates Hsp90, leading to Mps1 degradation and inactivation.
  • Hsp90 phosphorylation sensitizes cells to Hsp90 inhibitors, and elevated Mps1 levels confer selectivity to Hsp90 drugs in renal cell carcinoma.

Conclusions:

  • Mps1-mediated phosphorylation of Hsp90 is a key regulatory mechanism controlling chaperone activity and mitotic checkpoint function.
  • This regulatory axis provides a molecular basis for tumor sensitivity and selectivity to Hsp90 inhibitors.
  • Mps1 expression levels can serve as a predictive biomarker for patient response to Hsp90-targeted cancer therapies.
Keywords:
Cdc14Mps1heat shock protein-90kinasemitotic checkpointmolecular chaperonesphosphatasephosphorylationrenal cell carcinoma

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