title: 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.affiliation: 1] Institut National dela Santé et de la Recherche Médicale (Inserm) UMR866, Faculty of Medicine, Dijon, France [2] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France.
authors.forename: A
authors.initials: A
authors.lastname: Marivin
authors.affiliation: 1] Institut National dela Santé et de la Recherche Médicale (Inserm) UMR866, Faculty of Medicine, Dijon, France [2] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France.
authors.forename: J
authors.initials: J
authors.lastname: Berthelet
authors.affiliation: 1] Institut National dela Santé et de la Recherche Médicale (Inserm) UMR866, Faculty of Medicine, Dijon, France [2] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France.
authors.forename: J
authors.initials: J
authors.lastname: Cartier
authors.affiliation: 1] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France [2] Ecole Pratique des hautes études (EPHE), Dijon, France.
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.affiliation: 1] Institut National dela Santé et de la Recherche Médicale (Inserm) UMR866, Faculty of Medicine, Dijon, France [2] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France.
authors.forename: S
authors.initials: S
authors.lastname: Gemble
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Morizot
authors.affiliation: Institut FEMTO-ST, Université de Franche-Comté, CLIPP, Besançon, France.
authors.forename: W
authors.initials: W
authors.lastname: Boireau
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Saleh
authors.affiliation: 1] Inserm UMR749, Institut Fédératif de Recherche (IFR) 54, Villejuif, France [2] Institut Gustave Roussy, Institut Fédératif de Recherche (IFR) 54, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Bertoglio
authors.affiliation: 1] Institut Gustave Roussy, Institut Fédératif de Recherche (IFR) 54, Villejuif, France [2] UMR1009, Institut Fédératif de Recherche (IFR) 54, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Solary
authors.affiliation: 1] Institut National dela Santé et de la Recherche Médicale (Inserm) UMR866, Faculty of Medicine, Dijon, France [2] Université de Bourgogne; Institut Fédératif de Recherche (IFR) 100, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Dubrez
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000473:pathology; D011554:Pseudopodia / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020349:Surface Plasmon Resonance; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D014409:Tumor Necrosis Factor-alpha; D020764:cdc42 GTP-Binding Protein