Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification
Developmental Cell. 2010-10-01; 19(4): 521-532
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Hikasa H(1), Ezan J, Itoh K, Li X, Klymkowsky MW, Sokol SY.
(1)Department of Developmental and Regenerative Biology, Mount Sinai School of
Medicine, New York, NY 10029, USA.
A commonly accepted model of Wnt/β-catenin signaling involves target gene
activation by a complex of β-catenin with a T-cell factor (TCF) family member.
TCF3 is a transcriptional repressor that has been implicated in Wnt signaling and
plays key roles in embryonic axis specification and stem cell differentiation.
Here we demonstrate that Wnt proteins stimulate TCF3 phosphorylation in
gastrulating Xenopus embryos and mammalian cells. This phosphorylation event
involves β-catenin-mediated recruitment of homeodomain-interacting protein kinase
2 (HIPK2) to TCF3 and culminates in the dissociation of TCF3 from a target gene
promoter. Mutated TCF3 proteins resistant to Wnt-dependent phosphorylation
function as constitutive inhibitors of Wnt-mediated activation of Vent2 and Cdx4
during anteroposterior axis specification. These findings reveal an alternative
in vivo mechanism of Wnt signaling that involves TCF3 phosphorylation and
subsequent derepression of target genes and link this molecular event to a
specific developmental process.