title: Casein kinase 2 phosphorylation of Hsp90 threonine 22 modulates chaperone function and drug sensitivity.
abstract: The molecular chaperone Heat Shock Protein 90 (Hsp90) is essential for the function of various oncoproteins that are vital components of multiple signaling networks regulating cancer cell proliferation, survival, and metastasis. Hsp90 chaperone function is coupled to its ATPase activity, which can be inhibited by natural products such as the ansamycin geldanamycin (GA) and the resorcinol radicicol (RD). These compounds have served as templates for development of numerous natural product Hsp90 inhibitors. More recently, second generation, fully synthetic Hsp90 inhibitors, based on a variety of chemical scaffolds, have also been synthesized. Together, 18 natural product and synthetic Hsp90 inhibitors have entered clinical trial in cancer patients. To successfully develop Hsp90 inhibitors for oncology indications it is important to understand the factors that influence the susceptibility of Hsp90 to these drugs in vivo. We recently reported that Casein Kinase 2 phosphorylates a conserved threonine residue (T22) in helix-1 of the yeast Hsp90 N-domain both in vitro and in vivo. Phosphorylation of this residue reduces ATPase activity and affects Hsp90 chaperone function. Here, we present additional data demonstrating that ATP binding but not N-domain dimerization is a prerequisite for T22 phosphorylation. We also provide evidence that T22 is an important determinant of Hsp90 inhibitor sensitivity in yeast and we show that T22 phosphorylation status contributes to drug sensitivity in vivo.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. mollapourm@mail.nih.gov
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Yeong Sang
authors.initials: YS
authors.lastname: Kim
authors.forename: Jane
authors.initials: J
authors.lastname: Trepel
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D047390:Casein Kinase II / Q000378:metabolism*; D002986:Clinical Trials as Topic; D015195:Drug Design; D004351:Drug Resistance; D005656:Fungal Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D018832:Molecular Chaperones / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D012118:Resorcinols / Q000627:therapeutic use*; D013912:Threonine / Q000378:metabolism; D015003:Yeasts
chemical_list: D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D012118:Resorcinols; D013912:Threonine; D047390:Casein Kinase II