A smad action turnover switch operated by WW domain readers of a phosphoserine code Journal Article
| Authors: | Aragón, E.; Goerner, N.; Zaromytidou, A. I.; Xi, Q.; Escobedo, A.; Massague, J.; Macias, M. J. |
| Article Title: | A smad action turnover switch operated by WW domain readers of a phosphoserine code |
| Abstract: | When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-b pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-β signal delivery to turnover of the Smad signal transducers. © 2011 by Cold Spring Harbor Laboratory Press. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; unclassified drug; human cell; protein domain; protein function; bone morphogenetic protein; cyclin dependent kinase 8; cyclin dependent kinase 9; smad protein; smad1 protein; smad3 protein; transforming growth factor beta; protein metabolism; protein protein interaction; transcription initiation; protein binding; transcription factor; phosphorylation; transcription factors; nuclear proteins; gene expression regulation; amino acid sequence; molecular sequence data; protein synthesis; molecular recognition; transcription; transforming growth factor beta1; smad proteins; binding site; models, molecular; protein structure, tertiary; ubiquitin protein ligase nedd4; endosomal sorting complexes required for transport; ubiquitin-protein ligases; phosphoserine; glycogen synthase kinase 3; bmp; hek293 cells; nucleic acid binding protein; peptidylprolyl isomerase; smad; ww domains; peptidylprolyl isomerase pin1; smurf1 protein; transcription factor yap; ubiquitin protein ligase nedd4l; ww protein; tgf-? |
| Journal Title: | Genes and Development |
| Volume: | 25 |
| Issue: | 12 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2011-06-15 |
| Start Page: | 1275 |
| End Page: | 1288 |
| Language: | English |
| DOI: | 10.1101/gad.2060811 |
| PROVIDER: | scopus |
| PMCID: | PMC3127429 |
| PUBMED: | 21685363 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 17 August 2011" - "CODEN: GEDEE" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work