CELLULAR INTERPRETATION OF MULTIPLE TGF-BETA SIGNALS - INTRACELLULAR ANTAGONISM BETWEEN ACTIVIN BVG1 AND BMP-2/4 SIGNALING MEDIATED BY SMADS/

During early embryogenesis of Xenopus, dorsoventral polarity of the me soderm is established by dorsalizing and ventralizing agents, which ar e presumably mediated by the activity of an activin/BVg1-like protein and Bone Morphogenetic Proteins (BMP), respectively, Interestingly, th ese two TGF-beta subfamilies are found in overlapping regions during m esoderm patterning, This raises the question of how the presumptive me sodermal cells recognize the multiple TGF-beta signals and differentia lly interpret this information to assign a particular cell fate, In th is study; we have exploited the well characterized model of Xenopus me soderm induction to determine the intracellular interactions between B MP-2/4 and activin/BVg1 signaling cascades, Using a constitutively act ive BMP-2/4 receptor that transduces BMP-2/4 signals in a ligand-indep endent fashion, we demonstrate that signals provided by activin/BVg1 a nd BMP modulate each other's activity and that this crosstalk occurs t hrough intracellular mechanisms, In assays using BMP-2/4 and activin/B Vg1-specific reporters, we determined that the specificity of BMP-2/4 and activin/BVg1 signaling is mediated by Smad1 and Smad2, respectivel y, These Smads should be considered as the mediators of the intracellu lar antagonism between BMP-2/4 and activin/BVg1 signaling possibly thr ough sequestration of a limited pool of Smad4. Consistent with such a mechanism, Smad3 interacts functionally with both Smad1 and -2 to pote ntiate their signaling activities, and a dominant negative variant of Smad4 can inhibit both activin/BVg1 and BMP-2/4 mediated signaling Fin ally, we demonstrate that an activin/BVg1-dependent transcriptional co mplex contains both Smad2 and Smad4 and thereby provides a physical ba sis for the functional involvement of both Smads in TGF-P-dependent tr anscriptional regulation, Thus, Smad4 plays a central role in synergis tically activating activin/BVg1 and BMP-dependent transcription and fu nctions as an intracellular sensor for TGF-beta-related signals.