cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation

A Marivin, J Berthelet, J Cartier, C Paul, S Gemble, A Morizot, W Boireau, M Saleh, J Bertoglio, E Solary, L Dubrez

Research output: Contribution to journalArticlepeer-review

Abstract

Tumour necrosis factor-α (TNF) is a cytokine endowed with multiple functions, depending on the cellular and environmental context. TNF receptor engagement induces the formation of a multimolecular complex including the TNFR-associated factor TRAF2, the receptor-interaction protein kinase RIP1 and the cellular inhibitor of apoptosis cIAP1, the latter being essential for NF-κB activation. Here, we show that cIAP1 also regulates TNF-induced actin cytoskeleton reorganization through a cdc42-dependent, NF-κB-independent pathway. Deletion of cIAP1 prevents TNF-induced filopodia and cdc42 activation. The expression of cIAP1 or its E3-ubiquitin ligase-defective mutant restores the ability of cIAP1(-/-) MEFs to produce filopodia, whereas a cIAP1 mutant unable to bind TRAF2 does not. Accordingly, the silencing of TRAF2 inhibits TNF-mediated filopodia formation, whereas silencing of RIP1 does not. cIAP1 directly binds cdc42 and promotes its RhoGDIα-mediated stabilization. TNF decreases cIAP1-cdc42 interaction, suggesting that TNF-induced recruitment of cIAP1/TRAF2 to the receptor releases cdc42, which in turn triggers actin remodeling. cIAP1 also regulates cdc42 activation in response to EGF and HRas-V12 expression. A downregulation of cIAP1 altered the cell polarization, the cell adhesion to endothelial cells and cell intercalation, which are cdc42-dependent processes. Finally, we demonstrated that the deletion of cIAP1 regulated the HRas-V12-mediated transformation process, including anchorage-dependent cell growth, tumour growth in a xenograft model and the development of experimental metastasis in the lung.

Original languageEnglish
Pages (from-to)5534-45
Number of pages12
JournalOncogene
Volume33
Issue number48
DOIs
Publication statusPublished - 27 Nov 2014

Keywords

  • Actin Cytoskeleton
  • Animals
  • Blotting, Western
  • Cell Adhesion
  • Cell Polarity
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • Heterografts
  • Humans
  • Immunoprecipitation
  • Inhibitor of Apoptosis Proteins
  • Lung Neoplasms
  • Mice
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Pseudopodia
  • Signal Transduction
  • Surface Plasmon Resonance
  • Transfection
  • Tumor Necrosis Factor-alpha
  • cdc42 GTP-Binding Protein

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