9409665

pubmed:Citation

22

During early embryogenesis of Xenopus, dorsoventral polarity of the mesoderm is established by dorsalizing and ventralizing agents, which are presumably mediated by the activity of an activin/BVg1-like protein and Bone Morphogenetic Proteins (BMP), respectively. Interestingly, these two TGF-beta subfamilies are found in overlapping regions during mesoderm patterning. This raises the question of how the presumptive mesodermal cells recognize the multiple TGF-beta signals and differentially interpret this information to assign a particular cell fate. In this study, we have exploited the well characterized model of Xenopus mesoderm induction to determine the intracellular interactions between BMP-2/4 and activin/BVg1 signaling cascades. Using a constitutively active BMP-2/4 receptor that transduces BMP-2/4 signals in a ligand-independent fashion, we demonstrate that signals provided by activin/BVg1 and BMP modulate each other's activity and that this crosstalk occurs through intracellular mechanisms. In assays using BMP-2/4 and activin/BVg1-specific reporters, we determined that the specificity of BMP-2/4 and activin/BVg1 signaling is mediated by Smad1 and Smad2, respectively. These Smads should be considered as the mediators of the intracellular antagonism between BMP-2/4 and activin/BVg1 signaling possibly through sequestration of a limited pool of Smad4. Consistent with such a mechanism, Smad4 interacts functionally with both Smad1 and -2 to potentiate their signaling activities, and a dominant negative variant of Smad4 can inhibit both activin/BVg1 and BMP-2/4 mediated signaling Finally, we demonstrate that an activin/BVg1-dependent transcriptional complex contains both Smad2 and Smad4 and thereby provides a physical basis for the functional involvement of both Smads in TGF-beta-dependent transcriptional regulation. Thus, Smad4 plays a central role in synergistically activating activin/BVg1 and BMP-dependent transcription and functions as an intracellular sensor for TGF-beta-related signals.

eng

IM

MEDLINE

0950-1991

Print

NLM

4467-80

pubmed-meshheading:9409665-Activins, pubmed-meshheading:9409665-Animals, pubmed-meshheading:9409665-Base Sequence, pubmed-meshheading:9409665-Bone Morphogenetic Protein 2, pubmed-meshheading:9409665-Bone Morphogenetic Protein 4, pubmed-meshheading:9409665-Bone Morphogenetic Protein Receptors, pubmed-meshheading:9409665-Bone Morphogenetic Proteins, pubmed-meshheading:9409665-DNA Primers, pubmed-meshheading:9409665-DNA-Binding Proteins, pubmed-meshheading:9409665-Female, pubmed-meshheading:9409665-Goosecoid Protein, pubmed-meshheading:9409665-Homeodomain Proteins, pubmed-meshheading:9409665-Inhibins, pubmed-meshheading:9409665-Intracellular Fluid, pubmed-meshheading:9409665-Male, pubmed-meshheading:9409665-Polymerase Chain Reaction, pubmed-meshheading:9409665-Promoter Regions, Genetic, pubmed-meshheading:9409665-Receptors, Cell Surface, pubmed-meshheading:9409665-Receptors, Growth Factor, pubmed-meshheading:9409665-Repressor Proteins, pubmed-meshheading:9409665-Signal Transduction, pubmed-meshheading:9409665-Smad Proteins, pubmed-meshheading:9409665-Smad2 Protein, pubmed-meshheading:9409665-Smad4 Protein, pubmed-meshheading:9409665-Trans-Activators, pubmed-meshheading:9409665-Transcription Factors, pubmed-meshheading:9409665-Transforming Growth Factor beta, pubmed-meshheading:9409665-Xenopus, pubmed-meshheading:9409665-Xenopus Proteins

Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't