cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation.

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.

• Authors: A Marivin, J Berthelet, J Cartier, C Paul, S Gemble, A Morizot, W Boireau, M Saleh, J Bertoglio, E Solary, L Dubrez
• Journal: Oncogene (Oncogene) Vol. 33 Issue 48 Pg. 5534-45 (Nov 27 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24276241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inhibitor of Apoptosis Proteins
• Tumor Necrosis Factor-alpha
• cdc42 GTP-Binding Protein

Topics

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