cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation - Université de Bourgogne Accéder directement au contenu
Article Dans Une Revue Oncogene Année : 2013

cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation

Résumé

umour 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.

Dates et versions

hal-00920843 , version 1 (19-12-2013)

Identifiants

Citer

Arthur Marivin, Jean Berthelet, Jessy Cartier, Catherine Paul, Simon Gemble, et al.. cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation. Oncogene, 2013, pp.24276241. ⟨10.1038/onc.2013.499⟩. ⟨hal-00920843⟩
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