NDLI: Lefty Inhibits Receptor-regulated Smad Phosphorylation Induced by the Activated Transforming Growth Factor-β Receptor

Content Provider	Journal of Biological Chemistry (JBC)
Author	Ulloa, Luis Tabibzadeh, Siamak
Abstract	Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates growth and differentiation of diverse types of cells. TGF-β actions are directed by ligand-induced activation of TGF-β receptors with intrinsic serine/threonine kinase activity that trigger phosphorylation of receptor-regulated Smad (R-Smad) protein. Phosphorylated R-Smad proteins bind to Smad4, and the complexes formed move into the nucleus, where they act as components of a transcriptional complex. Here, we show that TGF-β signaling is inhibited by lefty, a novel member of the TGF-β superfamily. Lefty perturbed TGF-β signaling by inhibiting the phosphorylation of Smad2 following activation of the TGF-β receptor. Moreover, lefty inhibited the events that lie downstream from R-Smad phosphorylation, including heterodimerization of R-Smad proteins with Smad4 and nuclear translocation of the R-Smad·Smad4 complex. Lefty repressed TGF-β-induced expression of reporter genes for the p21,cdc25, and connective tissue growth factor promoters and of a reporter gene driven by the Smad-binding element. Similarly, lefty inhibited both BMP-mediated Smad5 phosphorylation and gene transcription. The action of lefty does not appear to depend on protein synthesis, including synthesis of inhibitory Smad proteins. Thus, lefty provides a repressed state of TGF-β- or BMP-responsive genes and participates in negative modulation of TGF-β and BMP signaling by inhibition of phosphorylation of R-Smad proteins.
Related Links	http://www.jbc.org/content/276/24/21397.abstract
Ending Page	21404
Starting Page	21397
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	24
Volume Number	276
DOI	10.1074/jbc.M010783200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2001-06-15
Access Restriction	Open
Subject Keyword	Transforming growth factor-β (TGF-β) Receptor-regulated Smad (R-Smad) Extracellular signal-regulated kinase (Erk) Janus kinase (Jak) Signal transducers and activators of transcription (Stat) Polyacrylamide gel electrophoresis (PAGE) Mitogen-activated protein kinase (MAPK) Bone morphogenetic protein (BMP) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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