The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling
Open accessAbstract
Summary TGFβ induces phosphorylation of the transcription factors Smad2 and Smad3 at the C-terminus as well as at an interdomain linker region. TGFβ-induced linker phosphorylation marks the activated Smad proteins for proteasome-mediated destruction. Here we identify Nedd4L as the ubiquitin ligase responsible for this step. Through its WW domain Nedd4L specifically recognizes a TGFβ-induced phosphoThr-ProTyr motif in the linker region, resulting in Smad2/3 poly-ubiquitination and degradation. Nedd4L is not interchangeable with Smurf1, a ubiquitin ligase that targets BMP-activated, linker-phosphorylated Smad1. Nedd4L limits the half-life of TGFβ activated Smads, restricts the amplitude and duration of TGFβ gene responses, and in mouse embryonic stem cells limits the induction of mesoendodermal fates by Smad2/3-activating factors. Hierarchical regulation is provided by SGK1, which phosphorylates Nedd4L to prevent binding of Smad2/3. Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGFβ signal transduction.
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Cites
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907
Self-citationSPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS
Feng, X.-H., & Derynck, R. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.022404.142018 · Cited by 1,869
Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways
Alarcón, C., Zaromytidou, A.-I., Xi, Q., Gao, S., Yu, J., Fujisawa, S., Barlas, A., Miller, A. N., Manova-Todorova, K., Macias, M. J., et al. (2009) · Cell · doi:10.1016/j.cell.2009.09.035 · Cited by 719
Self-citationPhosphorylation of Nedd4‐2 by Sgk1 regulates epithelial Na+ channel cell surface expression
Debonneville, C., Flores, S. Y., Kamynina, E., Plant, P. J., Tauxe, C., Thomas, M. A., Münster, C., Chraïbi, A., Pratt, J. H., Horisberger, J., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.24.7052 · Cited by 711
Cited by
Massagué, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3434 · Cited by 3,128
Self-citationControl of the Embryonic Stem Cell State
Young, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.01.032 · Cited by 1,197
The Mediator complex: a central integrator of transcription
Allen, B. L., & Taatjes, D. J. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3951 · Cited by 922
TGF-β signaling in health and disease
Massagué, J., & Sheppard, D. (2023) · Cell · doi:10.1016/j.cell.2023.07.036 · Cited by 890
Self-citationTGF-β Signaling from Receptors to Smads
Hata, A., & Chen, Y.-G. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022061 · Cited by 888
Metadata
- Authors
- Gao, S., Alarcón, C., Sapkota, G., Rahman, S., Chen, P.-Y., Goerner, N., Macias, M. J., Erdjument-Bromage, H., Tempst, P., & Massagué, J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 36
- Issue
- 3
- Pages
- 457-468
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2086711528
- Cited by
- 389
- References
- 4
- FWCI
- 8.28
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Gao, S., Alarcón, C., Sapkota, G., Rahman, S., Chen, P.-Y., Goerner, N., Macias, M. J., Erdjument-Bromage, H., Tempst, P., & Massagué, J. (2009). Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling. Molecular Cell. https://doi.org/10.1016/j.molcel.2009.09.043
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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