Balancing BMP Signaling through Integrated Inputs into the Smad1 Linker

Abstract

FGF and other Ras/MAPK pathway activators counterbalance BMP action during neurogenesis, bone formation, and other aspects of vertebrate development and homeostasis. BMP receptors signal through C-terminal phosphorylation and nuclear translocation of the transcription factor Smad1, whereas MAPKs catalyze inhibitory phosphorylation in the Smad1 linker region. Here we show that linker phosphorylation restricts Smad1 activity by enabling Smad1 recognition by the HECT-domain ubiquitin ligase Smurf1. Besides causing Smad1 polyubiquitination, Smurf1 binding inhibits the interaction of Smad1 with the nuclear translocation factor Nup214. Consequently, MAPK-dependent Smurf1 binding leads Smad1 alternatively to degradation or cytoplasmic retention. Smad1 linker phosphorylation and Smurf1 act as interdependent inputs to control BMP signaling during mouse osteoblast differentiation and Xenopus neural development. Linker phosphorylation is triggered also by BMP, providing feedback control. The interplay between linker phosphorylation, Smurf-dependent ubiquitination, and nucleoporin exclusion enables regulation of BMP action by diverse signals and biological contexts.

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

“…Recently, importance of the cross-talk between Ras and TGF-␤ signaling pathways has been reported, although roles of Ras signaling on TGF-␤ signaling appear to be context-dependent (Gotzmann et al, 2002;Peinado et al, 2003). Smad1 is phosphorylated by Ras-activated ERK MAP kinases and degraded by Smurf1 (Sapkota et al, 2007), whereas Smad2/3 are irregularly translocated to the nucleus in certain cancer cells transfected with active Ras (Yamagata et al, 2005;Oft et al, 2002). Interestingly, it was reported that TGF-␤-induced EMT was found only in the presence of active Ras (Gotzmann et al, 2002), suggesting that Ets1 would be a key molecule for the cross-talk between TGF-␤ and Ras signaling pathways.…”

To (TGF)β or not to (TGF)β: Fine-tuning of Smad signaling via post-translational modifications

“…Smurf1 was found to selectively bind to linker-phosphorylated Smad1. Not only did this result in the ubiquitination and specific degradation of linker-phosphorylated Smad1, Smurf1 binding also blocked nucleoporin-Smad1 interactions and subsequent Smad1 nuclear translocation [46]. These data finally provide one firm mechanism as to how linker phosphorylation can restrict Smad1 activity.…”

“…Originally discovered in a yeast two-hybrid screen using Smad1 as bait, Smurf1 can ubiquitinate BMPspecific Smads 1 and 5, but not TGF-β-specific Smads 2 and 3, targeting them for degradation [44,45]. A recent report by Sapkota et al elegantly demonstrates how different Smad posttranslational modifications can converge in regulating Smad signaling, by revealing interplay between Smad1 linker phosphorylation and Smurf1-dependent ubiquitination [46]. Smurf1 was found to selectively bind to linker-phosphorylated Smad1.…”

Activation of c-Jun NH2-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor

“…Further, the E-3 ligase Smurf1 has been shown to bind preferentially to Smad1 that is phosphorylated in the linker region, targeting it for degradation. (36) Recently, an additional level of complexity in understanding the importance of Smad1 linker-region phosphorylation has been added with the identification of R-Smad linker phosphatases that have site specificity. (37) Less is known about linker-region phosphorylation of Smad6.…”