Balancing BMP Signaling through Integrated Inputs into the Smad1 Linker Journal Article
| Authors: | Sapkota, G.; Alarcón, C.; Spagnoli, F. M.; Brivanlou, A. H.; Massague, J. |
| Article Title: | 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. © 2007 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein phosphorylation; carrier protein; unclassified drug; human cell; nonhuman; ubiquitin; mouse; animals; mice; animal tissue; cells, cultured; signaling; bone morphogenetic protein; bone morphogenetic protein receptor; smad1 protein; ubiquitin protein ligase; carboxy terminal sequence; embryo; hela cell; phosphorylation; vertebrata; ubiquitination; cell strain hek293; protein transport; cytoplasm; devbio; ras protein; feedback system; cell nucleus; ossification; catalysis; homeostasis; mitogen-activated protein kinases; nervous system development; ubiquitin-protein ligases; catalyst; fibroblast growth factor; fibroblast growth factors; osteoblast; xenopus; bone morphogenetic proteins; mitogens; glycogen synthase kinase 3; nuclear pore complex proteins; nucleoporin; protein nup214; ubiquitin ligase smurf1 |
| Journal Title: | Molecular Cell |
| Volume: | 25 |
| Issue: | 3 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2007-02-09 |
| Start Page: | 441 |
| End Page: | 454 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2007.01.006 |
| PUBMED: | 17289590 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 102" - "Export Date: 17 November 2011" - "CODEN: MOCEF" - "Source: Scopus" |
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