TAK1 is activated by two independent mechanisms in the regulation of epithelial cell survival

Abstract

TAK1 (TGF‐β‐activated kinase 1) is a key signaling intermediate in cytokines such as IL‐1 signaling leading to cell survival. We have previously reported that skin and intestinal epithelium‐specific TAK1 knockout mice are lethal in early neonatal stage due to accumulation of reactive oxygen species and subsequent induction of cell death. TAK1 has three high affinity binding proteins, TAB1, TAB2 and TAB3. TAB3 is structurally very similar to TAB2 and both TAB2 and TAB3 activate TAK1 through recruiting TAK1 to the polyubiquitin chains. TAB1 shares no homology with TAB2/3 and functions to oligomerize and activate TAK1. Although TAB2/3 have been reported to mediate TAK1 activation in cytokine signaling, we found that TAK1 activation was intact in TAB2 and TAB3 double‐deficient cells in response to IL‐1. Unexpectedly, we discovered that TAK1 activation was abolished in TAB1 and TAB2 double‐deficient cells. Furthermore, epithelium‐specific TAB1 and TAB2 double but not TAB1 or TAB2 single knockout mice phenocopied epithelium‐specific TAK1 knockout mice. TAK1 kinase activity was abolished in TAB1 and TAB2 knockout in vivo epithelial tissues, while it was maintained in TAB1 or TAB2 single knockout epithelium. These results demonstrate that TAB1‐ and TAB2‐mediated mechanisms independently activate TAK1 in the in vivo epithelial cells, and one mechanism is sufficient for maintenance of TAK1 activity.This work was supported by National Institutes of Health Grant GM068812 and GM084406 (to J. N‐T.)