The type III transforming growth factor- receptor negatively regulates nuclear factor kappa B signaling through its interaction with -arrestin2

Transforming growth factor-β (TGF-β) increases or decreases nuclear factor kappa B (NFκB) signaling in a context-dependent manner through mechanisms that remain to be defined. The type III transforming growth factor-β receptor (TβRIII) is a TGF-β superfamily co-receptor with emerging roles in both mediating and regulating TGF-β superfamily signaling. We have previously reported a novel interaction of TβRIII with the scaffolding protein, β-arrestin2, which results in TβRIII internalization and downregulation of TGF-β signaling. β-arrestin2 also scaffolds interacting receptors with the mitogen-activated protein kinase and NFκB-signaling pathways. Here, we demonstrate that TβRIII, through its interaction with β-arrestin2, negatively regulates NFκB signaling in MCF10A breast epithelial and MDA-MB-231 breast cancer cells. Increasing TβRIII expression reduced NFκB-mediated transcriptional activation and IκBα degradation, whereas a TβRIII mutant unable to interact with β-arrestin2, TβRIII-T841A, had no effect. In a reciprocal manner, short hairpin RNA-mediated silencing of either TβRIII expression or β-arrestin2 expression increased NFκB-mediated transcriptional activation and IκBα degradation. Functionally, TβRIII-mediated repression of NFκB signaling is important for TβRIII-mediated inhibition of breast cancer cell migration. These studies define a mechanism through which TβRIII regulates NFκB signaling and expand the roles of this TGF-β superfamily co-receptor in regulating epithelial cell homeostasis.