title: The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding.
abstract: Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. FNIPs compete with the activating co-chaperone Aha1 for binding to Hsp90, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Lastly, downregulation of FNIPs desensitizes cancer cells to Hsp90 inhibitors, whereas FNIPs overexpression in renal tumours compared with adjacent normal tissues correlates with enhanced binding of Hsp90 to its inhibitors. Our findings suggest that FNIPs expression can potentially serve as a predictive indicator of tumour response to Hsp90 inhibitors.
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Woodford
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Dunn
authors.affiliation: Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Blanden
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Dante
authors.initials: D
authors.lastname: Capriotti
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: David
authors.initials: D
authors.lastname: Loiselle
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London SE1 9NH, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: Health Sciences Library, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Wendi
authors.initials: W
authors.lastname: Ackerman
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Haystead
authors.affiliation: Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Stewart N
authors.initials: SN
authors.lastname: Loh
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bourboulia
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.|Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.
authors.forename: W
authors.initials: W
authors.lastname: Marston Linehan
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Gennady
authors.initials: G
authors.lastname: Bratslavsky
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.|Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C504459:FILIP1L protein, human; C476078:FLCN protein, human; C516440:FNIP1 protein, human; C529782:FNIP2 protein, human; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins