Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels.
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.
Kise
Yoshiaki
Y
Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Takenaka
Kei
K
Tezuka
Tohru
T
Yamamoto
Tadashi
T
Miki
Hiroaki
H
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
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