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

Taner Dogan1, Gregory S Harms, Mirko Hekman

  • 1Emmy Noether Group of DFG, Institut für Biochemie II, Goethe University Medical School, Frankfurt, Germany.

Nature Cell Biology
|November 18, 2008
PubMed

Insights

Inhibitor of apoptosis proteins (IAPs) regulate cell death. New findings reveal IAPs control C-RAF protein levels, impacting cell migration via the MAPK pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Inhibitor of apoptosis proteins (IAPs) are crucial regulators of cell survival.
  • C-RAF kinase is a key component of the RAS-RAF-MEK-ERK (MAPK) signaling pathway, controlling cell growth and survival.
  • The precise mechanisms governing C-RAF protein stability and its regulation by IAPs are not fully understood.

Purpose of the Study:

  • To investigate the interaction between IAPs (XIAP, c-IAPs) and C-RAF kinase.
  • To elucidate the role of IAPs in C-RAF protein turnover and its impact on cellular functions.
  • To explore the involvement of the Hsp90 machinery and CHIP in IAP-mediated C-RAF regulation.

Main Methods:

  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • siRNA-mediated gene silencing to assess the functional impact of IAPs and CHIP.
  • Western blotting to analyze protein levels and ubiquitylation status.
  • Cell migration assays to quantify migratory behavior.

Main Results:

  • XIAP and c-IAPs directly bind to C-RAF kinase.
  • Silencing XIAP or c-IAPs leads to C-RAF stabilization in human cells.
  • XIAP promotes C-RAF ubiquitylation via the Hsp90 system, independent of its E3 ligase activity.
  • XIAP facilitates CHIP binding to the C-RAF-Hsp90 complex, promoting C-RAF turnover.
  • Knockdown of XIAP, c-IAPs, or CHIP results in enhanced cell migration in a C-RAF-dependent manner.

Conclusions:

  • XIAP and c-IAPs play an unexpected role in regulating C-RAF protein stability.
  • IAP-mediated regulation of C-RAF impacts the MAPK pathway and cell migration.
  • This study reveals a novel mechanism controlling C-RAF turnover and highlights IAPs as potential modulators of cancer cell motility.

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