NDLI: Nucleocytoplasmic Shuttling of Smad1 Conferred by Its Nuclear Localization and Nuclear Export Signals

Content Provider	Journal of Biological Chemistry (JBC)
Author	Xiao, Zhan Watson, Nicki Rodriguez, Carlos Lodish, Harvey F.
Abstract	Smad1 mediates signaling by bone morphogenetic proteins (BMPs). In the resting state, Smad1 is found in both the nucleus and cytosol. BMP addition triggers Smad1 serine phosphorylation, binding of Smad4, and its accumulation in the nucleus. Mutations in the Smad1 N-terminal basic nuclear localization signal (NLS)-like motif, conserved among all Smad proteins, eliminated its ligand-induced nuclear translocation without affecting its other functions, including DNA binding and complex formation with Smad4. Addition of leptomycin B, an inhibitor of nuclear export, induced rapid nuclear accumulation of Smad1, whereas overexpression of CRM1, the receptor for nuclear export, resulted in Smad1 re-localization to the cytoplasm and inhibition of BMP-induced nuclear accumulation. Thus, in addition to the NLS, Smad1 also contains a functional nuclear export signal (NES). We identified a leucine-rich NES motif in the C terminus of Smad1; its disruption led to constitutive Smad1 nuclear distribution. Reporter gene activation assays demonstrated that both the NLS and NES are required for optimal transcriptional activation by Smad1. Despite its constitutive nuclear accumulation, a Smad1 NES mutant did not display higher basal reporter gene activity. We conclude that Smad1 is under constant nucleocytoplasmic shuttling conferred by its NLS and NES; nuclear accumulation after ligand-induced phosphorylation represents a change in the balance of the activities of these opposing signals and is essential for transcriptional activation.
Related Links	http://www.jbc.org/content/276/42/39404.abstract
Ending Page	39410
Starting Page	39404
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	42
Volume Number	276
DOI	10.1074/jbc.M103117200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2001-10-19
Access Restriction	Open
Subject Keyword	Transforming growth factor-β (TGF-β) Bone morphogenetic protein (BMP) Receptor-regulated Smad (R-Smad) Common Smad (Co-Smad) Inhibitory Smad (I-Smad) Nuclear localization signal (NLS) Nuclear export signal (NES) Mitogen-activated protein kinase (MAPK) Leptomycin B (LMB) Green fluorescent protein (GFP) Glutathione S-transferase (GST) Fluorescein isothiocyanate (FITC) Wild-type (WT) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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