Germ-Layer Specification and Control of Cell Growth by Ectodermin, a Smad4 Ubiquitin Ligase

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.

The role of FoxC1 in early Xenopus development

“…Some of these VegT targets are involved in specifying endodermal fate (GATA4, -5, -6, and XSox17; Xanthos et al, 2001), while others establish boundaries between the mesoderm and endodermal areas (Mixer; Kofron et al, 2004). A third group includes signaling molecules and antagonists that are essential for mesodermal fate specification (Xnrs, chordin, FGFs, Antivin;Tanegashima et al, 2000;Kofron et al, 1999;Cha et al, 2006), while a fourth group of targets is negatively regulated by VegT and is required for ectodermal specification (ectodermin, Xema; Dupont et al, 2005;Mir et al, 2007).…”

Regulation of Smad activities

“…Smad4 lacks a PPXY motif to recruit the Smurfs, however, ectodermin/TIF1-γ (also named TIM33, RFG7 and PTC7), a protein harboring a RING domain in addition to a number of other functional domains, was reported recently to suppress Smad4 function and impair Xenopus embryonic development by acting as an E3 ubiquitin ligase of Smad4 [90]. This hypothesis is somewhat controversial, as another recent study in mammals did not find ectodermin/TIF1-γ functions in Smad4 degradation, but rather that ectodermin/TIF1-γ competes with Smad4 as a transcription cofactor of R-Smads and regulates the development of the hematopoietic system [91].…”

To (TGF)β or not to (TGF)β: Fine-tuning of Smad signaling via post-translational modifications

“…Dupont et al identified Ectodermin as a RING-type ubiquitin ligase for Smad4 which acts to control TGF-β and BMP signaling in Xenopus embryo development, ensuring correct developmental cell fate [86]. Depletion of Ectodermin or over-expression of Smad4 in the embryo marginal zone results in the same developmental phenotype, in agreement with the idea that Smad4 is a key Ectodermin target.…”

“…Depletion of Ectodermin or over-expression of Smad4 in the embryo marginal zone results in the same developmental phenotype, in agreement with the idea that Smad4 is a key Ectodermin target. Strong biochemical evidence confirms Ectodermin is a ubiquitin E3 ligase for Smad4, and the authors further demonstrate a role for this ligase in limiting TGF-β-induced antiproliferative responses in human adult cells [86].…”