skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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:
 [1];  [1];  [2];  [2];  [3]
  1. Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan)
  2. Division of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan)
  3. Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan) and PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012 (Japan). E-mail: miki@ims.u-tokyo.ac.jp
Publication Date:
OSTI Identifier:
20857899
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 351; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2006.10.036; PII: S0006-291X(06)02221-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; DROSOPHILA; GROWTH; INHIBITION; LUCIFERASE; NEOPLASMS; PROSTATE; SERINE; THREONINE; TRANSCRIPTION FACTORS

Citation Formats

Kise, Yoshiaki, Takenaka, Kei, Tezuka, Tohru, Yamamoto, Tadashi, and Miki, Hiroaki. Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.10.036.
Kise, Yoshiaki, Takenaka, Kei, Tezuka, Tohru, Yamamoto, Tadashi, & Miki, Hiroaki. Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels. United States. doi:10.1016/j.bbrc.2006.10.036.
Kise, Yoshiaki, Takenaka, Kei, Tezuka, Tohru, Yamamoto, Tadashi, and Miki, Hiroaki. Fri . "Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels". United States. doi:10.1016/j.bbrc.2006.10.036.
@article{osti_20857899,
title = {Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels},
author = {Kise, Yoshiaki and Takenaka, Kei and Tezuka, Tohru and Yamamoto, Tadashi and Miki, Hiroaki},
abstractNote = {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.},
doi = {10.1016/j.bbrc.2006.10.036},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 351,
place = {United States},
year = {2006},
month = {12}
}