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Mol Cell
2012 Mar 09;455:619-28. doi: 10.1016/j.molcel.2011.12.032.
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XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling.
Hanson AJ, Wallace HA, Freeman TJ, Beauchamp RD, Lee LA, Lee E.
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A key event in Wnt signaling is conversion of TCF/Lef from a transcriptional repressor to an activator, yet how this switch occurs is not well understood. Here, we report an unanticipated role for X-linked inhibitor of apoptosis (XIAP) in regulating this critical Wnt signaling event that is independent of its antiapoptotic function. We identified DIAP1 as a positive regulator of Wingless signaling in a Drosophila S2 cell-based RNAi screen. XIAP, its vertebrate homolog, is similarly required for Wnt signaling in cultured mammalian cells and in Xenopus embryos, indicating evolutionary conservation of function. Upon Wnt pathway activation, XIAP is recruited to TCF/Lef where it monoubiquitylates Groucho (Gro)/TLE. This modification decreases affinity of Gro/TLE for TCF/Lef. Our data reveal a transcriptional switch involving XIAP-mediated ubiquitylation of Gro/TLE that facilitates its removal from TCF/Lef, thus allowing β-catenin-TCF/Lef complex assembly and initiation of a Wnt-specific transcriptional program.
Figure 3.
XIAP Is Required for Wnt Signaling In Vivo
(A) XIAP is required in Xenopus embryos for dorsal-anterior patterning. Embryos (four-cell stage) were injected dorsally with control (Con MO) or two independent XIAP morpholinos (XIAP MO #1 and #2) (25 ng), and dorsal-anterior index (DAI) was determined ( Kao and Elinson, 1988). The percentage of ventralized embryos (DAI ≤ 2) is graphed on the left (absolute numbers above bars) with representative embryos on the right. ∗p value < 0.0001 versus Con MO.
(B) Downregulating XIAP by morpholino injection inhibits Xwnt8-induced secondary axis formation. Embryos (four-cell stage) were coinjected ventrally with Xwnt8 mRNA (0.7 pg) plus control or XIAP morpholino (25 ng). The percentage of embryos with secondary axis formation is graphed on the left (absolute numbers above bars) with representative embryos on the right. ∗p value < 0.0001 versus Xwnt8/Con MO.
(C) XIAP is required for Xwnt8-induced expression of Wnt target genes in Xenopus ectodermal explants. Total RNA was extracted from animal caps coinjected with Xwnt8 mRNA (0.7 pg) and control or XIAP morpholino (25 ng), and Siamois and Xnr3 gene expression was assayed by RT-PCR. WE, whole embryo control; RT, reverse transcriptase. Ornithine decarboxylase (ODC) is loading control.
(D) XIAP induces secondary axis formation. Embryos (four-cell stage) were injected ventrally with control (Con) or XIAP mRNA (2 ng) and allowed to develop. The percentage of embryos with secondary axis formation is graphed on the left (absolute numbers above bars) with representative embryos on the right. ∗p value < 0.0001 versus Con.
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