title: Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads.
abstract: 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.
authors.affiliation: Department of Developmental and Cell Biology, and Developmental Biology Center, University of California at Irvine, 92717-2300, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Candia
authors.forename: T
authors.initials: T
authors.lastname: Watabe
authors.forename: S H
authors.initials: SH
authors.lastname: Hawley
authors.forename: D
authors.initials: D
authors.lastname: Onichtchouk
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Derynck
authors.forename: C
authors.initials: C
authors.lastname: Niehrs
authors.forename: K W
authors.initials: KW
authors.lastname: Cho
mesh_terms: D028341:Activins; D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D051956:Goosecoid Protein; D018398:Homeodomain Proteins; D007265:Inhibins / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D009414:Nerve Growth Factors; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; D015398:Signal Transduction; D051785:Smad Proteins; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051956:Goosecoid Protein; D018398:Homeodomain Proteins; C497402:MXD1 protein, Xenopus; D009414:Nerve Growth Factors; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; D051785:Smad Proteins; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D051901:Smad4 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525812:bmp4 protein, Xenopus; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D028341:Activins; D007265:Inhibins; D052004:Bone Morphogenetic Protein Receptors