Regulation of TCF3 by Wnt-dependent phosphorylation during vertebrate axis specification.
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.
Hikasa
Hiroki
H
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Ezan
Jerome
J
Itoh
Keiji
K
Li
Xiaotong
X
Klymkowsky
Michael W
MW
Sokol
Sergei Y
SY
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019521:Body Patterning / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C495248:wnt8a protein, Xenopus; D017346:Protein Serine-Threonine Kinases