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Vol. 10, Issue 10, 3151-3169, October 1999
§
*Molecular, Cellular, and Developmental Biology, University of
Colorado, Boulder, Boulder, Colorado, 80309-0347; and
§Division of Basic Sciences, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892
In Wnt signaling, 
-catenin and plakoglobin transduce signals to
the nucleus through interactions with TCF-type transcription factors.
However, when plakoglobin is artificially engineered to restrict it to
the cytoplasm by fusion with the transmembrane domain of connexin
(cnxPg), it efficiently induces a Wnt-like axis duplication phenotype
in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene
Siamois. Two models have been proposed to explain the
Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery
involved in the turnover of cytosolic -catenin, which then
accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly
acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined
their ability to induce an ectopic axis in Xenopus,
activate a TCF-responsive reporter (OT), stabilize -catenin, and
colocalize with components of the Wnt signaling pathway. cnxPg does not
colocalize with the Wnt pathway component Dishevelled, but it does lead
to the redistribution of APC and Axin, two proteins involved in the regulation of -catenin turnover. Expression of cnxPg increases levels of cytosolic -catenin; however, this effect does not
completely explain its signaling activity. Although cnxPg and Wnt-1
stabilize -catenin to similar extents, cnxPg activates OT to 10- to
20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4
synergize with -catenin and plakoglobin to activate OT, both
suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses
the signaling activity of both -catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of
Xenopus cells by cnxPg. Based on these data, we conclude
that, in addition to its effects on -catenin, cnxPg interacts with
other components of the Wnt pathway, perhaps TCFs, and that these
interactions contribute to its signaling activity.
These two authors contributed equally to
this manuscript.
Corresponding author. E-mail address:
klym{at}spot.colorado.edu.
Present address: Van Andel Research Institute, 201 Monroe Avenue NW, Suite 400, Grand Rapids, MI 49503.
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