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

作者：You Hye Jin; How Tam; Blobe Gerard C^*

来源：Carcinogenesis, 2009, 30(8): 1281-1287.

DOI：10.1093/carcin/bgp071

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

• 出版日期2009-8