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

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.

  1. Emmy Noether Group of the DFG, Institut für Biochemie II, Goethe University Medical School, Frankfurt, Germany.
  2. Bayerisches Krebsforschungszentrum, MZS, University of Würzburg, Germany.
  3. Department of Molecular Microscopy, Rudolf Virchow Center, University of Würzburg, Germany.
  4. Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
  5. These authors have contributed equally.

Correspondence to: Krishnaraj Rajalingam1,5 e-mail: krishna@biochem2.de

* In the version of this article initially published online, the label c-IAP-1 in Figure 1d was duplicated for both of the lower lines. The omitted c-IAP-2 label has been replaced in the HTML and PDF versions of the article.


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