PR130 is a modulator of the Wnt-signaling cascade that counters repression of the antagonist Naked cuticle

Abstract

The Wnt-signaling cascade is required for several crucial steps during early embryogenesis, and its activity is modulated by various agonists and antagonists to provide spatiotemporalspecific signaling. Naked cuticle is a Wnt antagonist that itself is induced by Wnt signaling to keep Wnt signaling in check. Little is known about the regulation of this antagonist. We have recently shown that the protein phosphatase 2A regulatory subunit PR72 is required for the inhibitory effect of Naked cuticle on Wnt signaling. In the present study, we show that PR130, which has an N terminus that differs from that of PR72 but shares the same C terminus, also interacts with Naked cuticle but instead functions as an activator of the Wnt-signaling pathway, both in cell culture and during development. We find that PR130 modulates Wnt signal transduction by restricting the ability of Naked cuticle to function as a Wnt inhibitor. Our data establish PR130 as a modulator of the Wntsignaling pathway and suggest a mechanism of Wnt signal regulation in which the inhibitory activity of Naked cuticle is determined by the relative level of expression of two transcripts of the same protein phosphatase 2A regulatory subunit.development ͉ protein phosphatase 2A ͉ Xenopus

Wnt/β-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency

“…The question of the roles of the two splice variants PR72 and PR130 in the switch from ''canonical'' to ''noncanonical'' wnt signaling appears to be quite complex. Recently, Creyghton et al (36) showed that unlike PR72, PR130 can antagonize some of the effects of Nkd in a variety of assays. However, PR130 morpholinos affected somite development and tail formation in Xenopus embryos (36).…”

“…Recently, Creyghton et al (36) showed that unlike PR72, PR130 can antagonize some of the effects of Nkd in a variety of assays. However, PR130 morpholinos affected somite development and tail formation in Xenopus embryos (36). The differential effects of IQ-1 on the two splice variants PR72 and PR130 and their roles in ''canonical'' to ''noncanonical'' Wnt signaling were not addressed in these studies and will require further analysis.…”

Protein Phosphatase 2A Is Targeted to Cell Division Control Protein 6 by a Calcium-binding Regulatory Subunit

“…This report showed that, in addition to the role of EF-hand 2 in interaction with the AC core dimer, calcium binding to EF-hand 1 increased the phosphatase activity of the PR72-holoenzyme toward DARPP-32 (32). Both PR72 and its alternative splice variant (PR130) have been reported to interact with the mammalian Naked cuticle protein and regulate Wnt signaling (33,34). Calcium may therefore influence Wnt signaling through recruitment and/or regulation of PP2A associated with Naked cuticle.…”

An Unconventional Nuclear Localization Motif Is Crucial for Function of the Drosophila Wnt/Wingless Antagonist Naked Cuticle

“…However, given the sequence divergence between insect and mammalian Nkds, their current mechanisms may share little similarity beyond Dsh binding. Recently, PR72 and PR130, two alternatively spliced B$ subunits of the multi-subunit enzyme protein phosphatase 2A (PP2A), were shown to associate with mammalian Nkd and to modulate its inhibitory effect on ectopic Wnt signaling (Creyghton et al 2005(Creyghton et al , 2006. As Dsh is phosphorylated by kinases such as CK1, CK2, and Par1 following Wnt stimulation (Yanagawa et al 1995;Willert et al 1997;Peters et al 1999;Sun et al 2001), recruitment of phosphatases to Dsh by Nkd represents an attractive hypothesis to embryos (D) stained with a-GFP (green).…”