Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase.
TGF-beta signaling is essential for development and proliferative homeostasis. During embryogenesis, maternal determinants act in concert with TGF-beta signals to form mesoderm and endoderm. In contrast, ectoderm specification requires the TGF-beta response to be attenuated, although the mechanisms by which this is achieved remain unknown. In a functional screen for ectoderm determinants, we have identified Ectodermin (Ecto). In Xenopus embryos, Ecto is essential for the specification of the ectoderm and acts by restricting the mesoderm-inducing activity of TGF-beta signals to the mesoderm and favoring neural induction. Ecto is a RING-type ubiquitin ligase for Smad4, a TGF-beta signal transducer. Depletion of Ecto in human cells enforces TGF-beta-induced cytostasis and, moreover, plays a causal role in limiting the antimitogenic effects of Smad4 in tumor cells. We propose that Ectodermin is a key switch in the control of TGF-beta gene responses during early embryonic development and cell proliferation.
Dupont
Sirio
S
Department of Histology, Microbiology and Medical Biotechnologies, Section of Histology and Embryology, University of Padua, 35121 Padua, Italy.
Zacchigna
Luca
L
Cordenonsi
Michelangelo
M
Soligo
Sandra
S
Adorno
Maddalena
M
Rugge
Massimo
M
Piccolo
Stefano
S
D000818:Animals; D001483:Base Sequence; D036703:Blastula / Q000166:cytology / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015723:Gene Library; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D017978:Receptors, Growth Factor; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000070584:Tripartite Motif Proteins; D029867:Xenopus Proteins; D044767:Ubiquitin-Protein Ligases; C500999:trim33 protein, Xenopus; D052004:Bone Morphogenetic Protein Receptors