title: Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels.
abstract: Serine/threonine kinase Fused (Fu) is an essential component of Hedgehog (Hh) signaling in Drosophila, but the biochemical functions of Fu remain unclear. Here, we have investigated proteins co-precipitated with mammalian Fu and identified a kinase-specific chaperone complex, Cdc37/Hsp90, as a novel-binding partner of Fu. Inhibition of Hsp90 function by geldanamycin (GA) induces rapid degradation of Fu through a ubiquitin-proteasome pathway. We next show that co-expression of Fu with transcription factors Gli1 and Gli2 significantly increases their protein levels and luciferase reporter activities, which are blocked by GA. These increases can be ascribed to Fu-mediated stabilization of Gli because co-expression of Fu prolongs half-life of Gli1 and reduces polyubiquitination of Gli1. Finally, we show that GA inhibits proliferation of PC3, a Hh signaling-activated prostate cancer cell line. This growth inhibition is partially rescued by expression of ectopic Gli1, suggesting that Fu may contribute to enhance Hh signaling activity in cancer cells.
authors.affiliation: Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kise
authors.forename: Kei
authors.initials: K
authors.lastname: Takenaka
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miki
mesh_terms: D000818:Animals; D060466:Axin Protein; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004795:Enzyme Stability; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
chemical_list: D060466:Axin Protein; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; C498520:Gli1 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; D012097:Repressor Proteins; D000071676:Zinc Finger Protein GLI1