The Human Frizzled 6 (HFz6) Acts as a Negative Regulator of the Canonical Wnt·β-Catenin Signaling Cascade

Abstract

Previously we have cloned the human Frizzled 1 (HFz1) and shown that it transmits the Wnt-3a-induced canonical pathway. We also cloned the human Frizzled 6 (HFz6) and show in the present study that, as opposed to HFz1, HFz6 did not activate the canonical Wnt pathway following exposure to various Wnts, whether belonging to the Wnt-1 or to the Wnt-5a group. Moreover we show that HFz6 repressed Wnt-3a-induced canonical signaling when co-expressed with HFz1. HFz6 repressed the canonical Wnt cascade activated also by various Wnt signaling intracellular mediators such as Dishevelled-1, a stabilized ␤-catenin(S33Y) mutant, and LiCl-mediated repression of glycogen synthase kinase-3␤ activity. Removal of HFz6 N -or C -terminal sequences abolished HFz6 repressive activity. As the HFz6 repressive effect was not associated with a decrease in the level of ␤-catenin, it is suggested that HFz6 does not affect ␤-catenin stabilization, implying that HFz6 transmits a repressive signaling that cross-talks with and inhibits the canonical Wnt pathway downstream of ␤-catenin destruction complex. HFz6 did not affect the level of nuclear T-cell factor 4 (TCF4) nor did it affect ␤-catenin⅐TCF4 complex formation. However, electrophoretic mobility shift assays indicated that HFz6 repressed the binding of TCF/ lymphoid enhancer factor transcription factors to target DNA. Moreover we present data suggesting that HFz6 activates the transforming growth factor-␤-activated kinase-NEMO-like kinase pathway that blocks TCF/lymphoid enhancer factor binding to target promoters, thereby inhibiting the ability of ␤-catenin to activate transcription of Wnt target genes.

Canonical Wnt activity regulates trunk neural crest delamination linking BMP/noggin signaling with G1/S transition

“…These, in turn, might have resulted in an adverse phenotype because they triggered inhibitory feedback mechanisms or receptors (e.g. Golan et al, 2004). Even under these conditions, the association between G1/S transition and NC delamination that we have previously found (Burstyn-Cohen and was maintained.…”

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

“…Fzd6, a member of the Frizzled wnt receptor family, has also been reported to repress Wnt signaling. 22 Lzic, leucin zipper and ICAT homologous domain, is a recently discovered gene proposed to inhibit the interaction between b-catenin and Tcf transcription factors like ICAT, inhibitor of Catenin and Tcf. 23 Ctnna1 (a-catenin) also can block the interaction between the b-catenin/Tcf/DNA complex.…”

Central Immune Senescence, Reversal Potentials

“…Fz1 and Fz6 are, for example, able to transmit inhibitory Wnt signals. While Fz1 inhibits Wnt signal transduction via a G-protein dependent manner (Roman-Roman et al 2004) (Zilberberg et al 2004), Fz6 (Golan et al 2004) inhibits Wnt dependent gene transcription by activating the transforming growth factor -activated kinase 1 (TAK1), a member of the MAPKKK family, and nemo-like kinase (NLK) (Ishitani et al 2003;Smit et al 2004) via a Ca ++ dependent signalling cascade. NLK phosphorylates TCF that consequently cannot bind to -catenin, and the formation of active transcription complex becomes inhibited (Smit et al 2004) .…”