Wise retained in the endoplasmic reticulum inhibits Wnt signaling by reducing cell surface LRP6

Abstract

The Wnt signaling pathway is tightly regulated by extracellular and intracellular modulators. Wise was isolated as a secreted protein capable of interacting with the Wnt co-receptor LRP6. Studies in Xenopus embryos revealed that Wise either enhances or inhibits the Wnt pathway depending on the cellular context. Here we show that the cellular localization of Wise has distinct effects on the Wnt pathway readout. While secreted Wise either synergizes or inhibits the Wnt signals depending on the partner ligand, ER-retained Wise consistently blocks the Wnt pathway. ER-retained Wise reduces LRP6 on the cell surface, making cells less susceptible to the Wnt signal. This study provides a cellular mechanism for the action of Wise and introduces the modulation of cellular susceptibility to Wnt signals as a novel mechanism of the regulation of the Wnt pathway.

Snail2 controls mesodermal BMP/Wnt induction of neural crest

“…For example, it appears that the secreted Wnt inhibitors Dkk1 and Sost are regulated by BMP signaling (Kamiya et al, 2010) and that BMP signaling requires functional Wnt signaling (Tang et al, 2009). The Wnt signaling modulator Lpr4 interacts with Wise, a secreted and endoplasmic reticulum-localized protein that can either enhance or inhibit Wnt signaling (Guidato and Itasaki, 2007;Guidato et al, 1996;Itasaki et al, 2003). The Lrp4-Wise complex can, in turn, modulate BMP activity (Lintern et al, 2009;Ohazama et al, 2010).…”

A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

“…USAG-1, the murine ortholog of SOSTDC1, binds to BMPs-2, -4, and -7 and antagonizes BMP activity in Xenopus embryos (Yanagita et al, 2004). Wise, another ortholog of SOSTDC1 identified in chick and Xenopus, can both activate and antagonize Wnt signaling during Xenopus development (Itasaki et al, 2003;Guidato and Itasaki, 2007).…”

“…Classical BMP antagonists bind BMPs in the extracellular space, preventing the association of BMPs with their receptors. BMP antagonists may also prevent the activity of BMPs by fostering their retention in the endoplasmic reticulum (ER; Guidato and Itasaki, 2007). BMP antagonists have been postulated to act as the key on/off switches that spatially and temporally regulate local BMP activity.…”

“…In addition to their effects on BMP pathways, BMP antagonists have also been reported to impinge on Wnt signaling, For example, sclerostin exerts its inhibitory effects on bone formation in mice primarily through inhibition of Wnt signaling (van Bezooijen et al, 2007); in Xenopus, the BMP antagonist Wise inhibits or stimulates Wnt signaling in a manner dependent on context (Itasaki et al, 2003) and cellular localization (Guidato and Itasaki, 2007). Several genes have been implicated in the development of renal clear cell carcinoma.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…2E) (Itasaki et al 2003). Not only secreted Wise is able to inhibit Wnt signaling, but endoplasmic reticulum (ER)-retained Wise is also able to do so by reducing cell surface LRP6 (Guidato and Itasaki 2007). Wise also binds the LRP4 receptor (Ohazama et al 2008), which is able to modulate Wnt signaling mediated by LRP5 and -6 (Ohazama et al 2008;Li et al 2010).…”