The TGFbeta superfamily regulates cell growth and differentiation. During Xenopus development, Nodal, Vg1 and activin-related signals induce endoderm and mesoderm, and BMP signals pattern these tissues and regulate ectodermal cell fate. The TGFbeta/activin and BMP pathways respectively transduce signals via Smads 2 and 3, or Smads1, 5 and 8. Little is known about TGFbeta signal downregulation. We have discovered two E3 ubiquitin ligases, Smurf1 and Smurf2, that inhibit BMP and TGFbeta/activin pathways, respectively (Zhu et al., 1999, Kavsak et al., 2000). Smurfs target Smads and receptors for ubiquitination and proteasomal degradation. While Smurf1 dorsalizes embryonic cell fates, the action of Smurf2 in embryos is unknown. We hypothesize that the Smurfs regulate tissue induction and pattern formation in embryogenesis by region-specific antagonism of TGFbeta signaling components. We will examine the role of Smurf1 and Smurf2 during embryogenesis and investigate the biochemical mechanisms necessary for Smurf regulation of development. Insight into Smurf functions will yield vital information about TGFbeta signaling and early development and will address pathologies such as birth defects, tissue degeneration and cancer, that result from defective regulation of TGFbeta signals or ubiquitin ligase functioning.
Aim 1. Do the Smurfs function in Xenopus embryonic development? We will establish the spatial distribution of Smurf proteins during embryogenesis, and determine the developmental effects of perturbing Smurf protein levels or activity.
Aim 2. How do Smurfs and TGFbeta signals regulate each other? To understand which signaling pathways Smurfs regulate in embryos, we will test the effects of Smurfs on components of BMP and activin signaling pathways, using biological (phenotype) and biochemical (interaction, ubiquitination) assays. We will determine whether Smurfs are regulated by TGFbeta, or other inductive signals, during development.
Aim 3. Identification and function of new Smurf interacting proteins. To obtain a comprehensive view of Smurf substrates and to find potential Smurf regulators, we will screen for and characterize Smurf-interacting proteins. We have already isolated 89 Smurf1-interacting clones, including Smad1, a known Smurf1 target.
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