X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility

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2008
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Dogan, Taner
Harms, Gregory S.
Hekman, Mirko
Oberoi, Tripat Kaur
Alnemri, Emad S.
Rapp, Ulf R.
Rajalingam, Krishnaraj
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Nature cell biology. 2008, 10(12), pp. 1447-1455. ISSN 1465-7392. eISSN 1476-4679. Available under: doi: 10.1038/ncb1804
Zusammenfassung

Inhibitor of apoptosis proteins (IAP) are evolutionarily conserved anti-apoptotic regulators. 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 survival. 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.

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570 Biowissenschaften, Biologie
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ISO 690DOGAN, Taner, Gregory S. HARMS, Mirko HEKMAN, Christiaan KARREMAN, Tripat Kaur OBEROI, Emad S. ALNEMRI, Ulf R. RAPP, Krishnaraj RAJALINGAM, 2008. X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility. In: Nature cell biology. 2008, 10(12), pp. 1447-1455. ISSN 1465-7392. eISSN 1476-4679. Available under: doi: 10.1038/ncb1804
BibTex
@article{Dogan2008-12Xlink-38710,
  year={2008},
  doi={10.1038/ncb1804},
  title={X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility},
  number={12},
  volume={10},
  issn={1465-7392},
  journal={Nature cell biology},
  pages={1447--1455},
  author={Dogan, Taner and Harms, Gregory S. and Hekman, Mirko and Karreman, Christiaan and Oberoi, Tripat Kaur and Alnemri, Emad S. and Rapp, Ulf R. and Rajalingam, Krishnaraj},
  note={There is an Erratum (January 2009) associated with this Article : Nature Cell Biology 11, 110 (2009), http://dx.doi.org/10.1038/ncb0109-110}
}
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There is an Erratum (January 2009) associated with this Article : Nature Cell Biology 11, 110 (2009), http://dx.doi.org/10.1038/ncb0109-110
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