Cellular inhibitor of apoptosis-1 (cIAP1) is a signaling regulator with oncogenic properties. It is involved in the regulation of signaling pathways controlling
inflammation, cell survival, proliferation, differentiation and motility. It is recruited into membrane-receptor-associated signaling complexes thanks to the molecular adaptor
TRAF2. However, the cIAP1/
TRAF2 complex exists, independently of receptor engagement, in several subcellular compartments. The present work strengthens the importance of
TRAF2 in the oncogenic properties of cIAP1. cIAPs-deficient mouse embryonic fibroblasts (MEFs) were transformed using the HRas-V12 oncogene. Re-expression of cIAP1 enhanced
tumor growth in a nude mice xenograft model, and promoted lung
tumor nodes formation. Deletion or mutation of the TRAF2-binding site completely abolished the oncogenic properties of cIAP1. Further, cIAP1 mediated the clustering of
TRAF2, which was sufficient to stimulate
tumor growth. Our
TRAF2 interactome analysis showed that cIAP1 was critical for
TRAF2 to bind to its
protein partners. Thus, cIAP1 and
TRAF2 would be two essential subunits of a signaling complex promoting a pro-tumoral signal. cIAP1/
TRAF2 promoted the activation of the canonical NF-κB and ERK1/2 signaling pathways. NF-κB-dependent production of
IL-6 triggered the activation of the JAK/STAT3 axis in an autocrine manner. Inhibition or downregulation of STAT3 specifically compromised the growth of cIAP1-restored MEFs but not that of MEFs expressing a cIAP1-mutant and treating mice with the STAT3 inhibitor
niclosamide completely abrogated cIAP1/
TRAF2-mediated
tumor growth. Altogether, we demonstrate that cIAP1/
TRAF2 binding is essential to promote
tumor growth via the activation of the JAK/STAT3 signaling pathway.