Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal

Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, CA 90095-1662, USA.
Cell (Impact Factor: 32.24). 12/2007; 131(5):980-93. DOI: 10.1016/j.cell.2007.09.027
Source: PubMed


BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.

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Available from: Luis C Fuentealba,
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    • "(Fuentealba et al., 2007 "
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    • "Furthermore, both the BMP and Activin pathways have been shown to interact with the canonical Wnt pathway during development, by direct proteinprotein interactions and by transcriptional regulation (reviewed in Guo and Wang, 2009). Smad1 phosphorylation is stabilized by Wnt signaling (Fuentealba et al., 2007), and activated Smad1, Smad2, and Smad3 have been shown to complex with b-catenin to regulate gene transcription (Labbé et al., 2000). Therefore, it is possible that inhibition of both BMP and Activin signals could have a secondary effect on Wnt signaling, however the significance of this effect remains unknown. "
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    • "Its primary phosphorylation by MAPK allows the secondary phosphorylation by GSK-3β, which lies at the intersection of several prominent signaling pathways which are instrumental in determining cell fate. They are also leading to polyubiquitination and the subsequent degradation of smad1, thus abolishing this pathway (Fuentealba et al., 2007; Pera et al., 2003) (Fig. 1). "
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