Transforming growth factor beta signalling in vitro and in vivo: activin ligand-receptor interaction, Smad5 in vasculogenesis, and repression of target genes by the delta EF1/ZEB-related SIP1 in the vertebrate embryo

The identification and characterization of components of the transforming g rowth factor beta (TGF beta) signalling pathway are proceeding at a very fa st pace. To illustrate a number of our activities in this field, we first s ummarize our work aiming at the selection from a large collection of single residue substitution mutants of two activin A polypeptides in which D27 an d K102, respectively, have been modified. This work has highlighted the imp ortance of K102 and its positive charge for binding to activin type II rece ptors. Activin K102E, which did not bind to high-affinity receptor complexe s, may be a valuable beta chain, when incorporated in recombinant inhibin t o unambiguously detect novel inhibin binding sites at the cell surface. We then illustrate how Smad5 knockout mice and an overexpression approach with a truncated TGF beta type II receptor in the mouse embryo can contribute t o the identification of a novel TGF beta --> T beta RII/ALK1 --> Smad5 path way in endothelial cells in the embryo proper and the yolk sac vasculature. We conclude with a summary of our results with a Smad-interacting transcri ptional repressor but focus on its biological significance in the vertebrat e embryo. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.