title: Heat shock protein 90 regulates phosphatidylinositol 3-kinase-related protein kinase family proteins together with the RUVBL1/2 and Tel2-containing co-factor complex.
abstract: Heat shock protein 90 (Hsp90), a conserved molecular chaperone for a specific set of proteins critical for signal transduction including several oncogenic proteins, has been recognized as a promising target for anticancer therapy. Hsp90 inhibition also sensitizes cancer cells to DNA damage. However, the underlying mechanisms are not fully understood. Here, we provide evidence that Hsp90 is a general regulator of phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins, central regulators of stress responses including DNA damage. Inhibition of Hsp90 causes a reduction of all PIKK and suppresses PIKK-mediated signaling. In addition, Hsp90 forms complexes with RUVBL1/2 complex and Tel2 complex, both of which have been shown to interact with all PIKK and control their abundance and functions. These results suggest that Hsp90 can form multiple complexes with the RUVBL1/2 complex and Tel2 complex and function in the regulation of PIKK, providing additional rationale for the effectiveness of Hsp90 inhibition for anticancer therapy, including sensitization to DNA damage.
authors.affiliation: Department of Molecular Biology, School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Izumi
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hirano
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins; D004265:DNA Helicases; D018841:HSP90 Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D050783:Proto-Oncogene Proteins c-ets; C409823:ETV7 protein, human; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human