TAB2 Scaffolds TAK1 and NLK in Repressing Canonical Wnt Signaling

Abstract

The TAK1-NLK cascade is a mitogen-activated protein kinase-related pathway that plays an inhibitory role in canonical Wnt/␤-catenin signaling through regulating the LEF1/TCF family transcriptional factors. TAB2 (TAK1-binding protein 2) is a putative TAK1 interacting protein that is involved in the regulation of TAK1. Here, we found that TAB2 could directly interact with NLK and function as a scaffold protein to facilitate the interaction between TAK1 and NLK. Knocking down TAB2 using small interfering RNA abolished the interaction of TAK1 with NLK in mammalian cells. The intermediate region (residues 292-417) of TAB2 was mapped for its binding to NLK. TAB2-⌬M, a TAB2 mutant lacking this region, showed a lower affinity for NLK and became defective in its scaffolding function. In addition, TAB2, but not TAB2-⌬M, mediated TAK1-dependent activation of NLK and LEF1 polyubiquitylation, resulting in the inhibition of canonical Wnt signaling. Moreover, Wnt3a stimulation led to an increase in the interaction of TAB2 with NLK and the formation of a TAK1⅐TAB2⅐NLK complex, suggesting that this TAK1-TAB2-NLK pathway may constitute a negative feedback mechanism for canonical Wnt signaling.

Genetic parameters and genome-wide association study of hyperpigmentation of the visceral peritoneum in chickens

“…MAP3K7 can also interact with many genes affecting melanocyte development [31,32], such as MITF [41], KIT ligand, B-cell leukemia/lymphoma 2 [42,43], lymphoid enhancer binding factor 1 [44], and epidermal growth factor receptor [45,46]. MAP3K7IP1 is one of the MAP3K7 binding proteins.…”

Nemo‐like kinase inhibits osteoblastogenesis by suppressing bone morphogenetic protein and WNT canonical signaling

“…In immortalized human cell culture systems, Nlk is activated by the non-canonical WNT Ca 2þ pathway, resulting in phosphorylation and degradation of Tcf and inhibition of the canonical WNT signaling pathway [Ishitani et al, 2003;Smit et al, 2004;Yamada et al, 2006;Li et al, 2010]. These studies were critical to demonstrate that mammalian cells possess the machinery necessary for the inhibitory action of Nlk on Tcf transactivation, but did not analyze the biological consequences of this effect.…”

“…Although nmo antagonizes WNT canonical signaling in Drosophila during wing development, the mechanism of this process is not known [Zeng and Verheyen, 2004]. In Caenorhabditis elegans and Xenopus laevis Nlk phosphorylates and targets Tcf for ubiquitinylation and proteasomal degradation, and as a consequence inhibits WNT canonical signaling [Ishitani et al, 1999[Ishitani et al, , 2003Smit et al, 2004;Yamada et al, 2006;Li et al, 2010]. Suppression of BMP/Smad and WNT canonical signaling by Nlk has been reported in mammalian immortalized cell culture models and human cancer cell lines; however, it is not known whether these effects are biologically relevant or occur in untransformed mammalian cells [Smit et al, 2004;Yamada et al, 2006;Zeng et al, 2007;Li et al, 2010].…”

The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein

“…After 18 h of transfection, cells were treated with Wnt3a conditioned medium (Wnt3a-CM) or control medium (Ctrl-CM) for an additional 6 h. Cells were then lysed, and luciferase assays were performed. The luciferase activities presented were normalized against the levels of GFP expression as described previously (20). Wnt3a-CM and Ctrl-CM were described previously (24).…”