Smith lab Developmental Biology Laboratory
: The regulation of TGFb and Wnt Signalling
Introduction
We are investigating the roles that TGFb and Wnt signalling play in the formation of the body axis and generation and patterning of the three germ layers: endoderm, mesoderm and ectoderm.
The TGF-b superfamily of growth factors, which include Nodals/Activin and Bone Morphogenetic Proteins (BMPs), are essential for early vertebrate development. They play a pivotal role in the formation of the body axis and generation and patterning of the three germ layers: endoderm, mesoderm and ectoderm.
Signalling is transmitted through type I and type II transmembrane serine/threonine kinase receptors by phosphorylating receptor regulated R-Smads: Smad 2 and 3 in the case of TGF-b (Nodals/Activin) and Smad 1, 5 and 8 for BMPs. In the canonical pathway, activated rSmads, bound in homo- or heteromeric complexes with a common partner Smad4, translocate into the nucleus where they regulate transcription of target genes. Although poorly understood, BMPs can also signal independently of Smad4.
Not surprisingly, TGF-b superfamily signalling is kept under tight control either through the control of ligand accessibility or by attenuating activated receptors and Smads via a variety of mechanisms.
We are interested in identifying mechanisms regulating TGF-b superfamily signalling and asking how these mechanisms influence the induction and patterning of the primary germ layers. One approach is to unearth new molecules that either modulate Smad activity or regulate their intracellular trafficking and turnover.
Figure 1: Canonical TGF-β superfamily signalling activates gene transcription via phosphorylated r-Smad/Smad4 complexes, while in non-canonical signalling phosphorylated r-Smads form active complexes with PAWS. (B, C) USP15 enhances BMP signalling (B) knockdown of xUSP15 reduces BMP-dependent Smad1 phosphorylation. (C) xUSP15 stabilises levels of Alk3 by targeting it for deubiquitylation.
