Letter abstract
Nature Cell Biology 10, 1447 - 1455 (2008)
Published online: 16 November 2008 | Corrected online: 24 November 2008 | doi:10.1038/ncb1804
There is an Erratum (January 2009) associated with this Article.
X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility
Taner Dogan1, Gregory S. Harms3, Mirko Hekman2, Christiaan Karreman2, Tripat Kaur Oberoi1, Emad S. Alnemri4, Ulf R. Rapp2,5 & Krishnaraj Rajalingam1,5
Abstract
Inhibitor of apoptosis proteins (IAP) are evolutionarily conserved anti-apoptotic regulators1, 2. C-RAF protein kinase is a direct RAS effector protein, which initiates the classical mitogen-activated protein kinase (MAPK) cascade. This signalling cascade mediates diverse biological functions, such as cell growth, proliferation, migration, differentiation and survival3, 4. Here we demonstrate that XIAP and c-IAPs bind directly to C-RAF kinase and that siRNA-mediated silencing of XIAP and c-IAPs leads to stabilization of C-RAF in human cells. XIAP binds strongly to C-RAF and promotes the ubiquitylation of C-RAF in vivo through the Hsp90-mediated quality control system, independently of its E3 ligase activity. In addition, XIAP or c-IAP-1/2 knockdown cells showed enhanced cell migration in a C-RAF-dependent manner. XIAP promotes binding of CHIP (carboxy terminal Hsc70-interacting protein), a chaperone-associated ubiquitin ligase, to the C-RAF–Hsp90 complex in vivo. Interfering with CHIP expression resulted in stabilization of C-RAF and enhanced cell migration, as observed in XIAP knockdown cells. Our data show an unexpected role of XIAP and c-IAPs in the turnover of C-RAF protein, thereby modulating the MAPK signalling pathway and cell migration.
- Emmy Noether Group of the DFG, Institut für Biochemie II, Goethe University Medical School, Frankfurt, Germany.
- Bayerisches Krebsforschungszentrum, MZS, University of Würzburg, Germany.
- Department of Molecular Microscopy, Rudolf Virchow Center, University of Würzburg, Germany.
- Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
- These authors have contributed equally.
Correspondence to: Krishnaraj Rajalingam1,5 e-mail: krishna@biochem2.de
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