Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase

Cell. 2005 Apr 8;121(1):87-99. doi: 10.1016/j.cell.2005.01.033.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blastula / cytology
  • Blastula / metabolism*
  • Bone Morphogenetic Protein Receptors
  • Cell Differentiation / physiology
  • Cell Nucleus / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Colon / cytology
  • Colon / metabolism
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Library
  • Germ Layers / cytology
  • Germ Layers / metabolism*
  • Humans
  • Molecular Sequence Data
  • Receptors, Growth Factor / metabolism
  • Signal Transduction / physiology
  • Smad4 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Xenopus / embryology
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Receptors, Growth Factor
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Tripartite Motif Proteins
  • Xenopus Proteins
  • Ubiquitin-Protein Ligases
  • trim33 protein, Xenopus
  • Bone Morphogenetic Protein Receptors

Associated data

  • GENBANK/AY781409