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J. Biol. Chem., Vol. 278, Issue 1, 428-437, January 3, 2003
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From the Bone morphogenetic proteins (BMPs) are members of
the transforming growth factor- The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF115498.
SANE, a Novel LEM Domain Protein, Regulates Bone Morphogenetic
Protein Signaling through Interaction with Smad1*
,§¶
, and Cell & Molecular Biology Graduate Group, the
§ Department of Medicine, and the ¶ Howard Hughes
Medical Institute, the University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104
(TGF-) superfamily that play
important roles in bone formation, embryonic patterning, and
epidermal-neural cell fate decisions. BMPs signal through pathway
specific mediators such as Smads1 and 5, but the upstream regulation of
BMP-specific Smads has not been fully characterized. Here we report the
identification of SANE (Smad1 Antagonistic
Effector), a novel protein with significant sequence
similarity to nuclear envelop proteins such as MAN1. SANE binds to
Smad1/5 and to BMP type I receptors and regulates BMP signaling. SANE
specifically blocks BMP-dependent signaling in
Xenopus embryos and in a mammalian model of bone formation but does not inhibit the TGF-/Smad2 pathway. Inhibition of BMP signaling by SANE requires interaction between SANE and Smad1, because
a SANE mutant that does not bind Smad1 does not inhibit BMP signaling.
Furthermore, inhibition appears to be mediated by inhibition of
BMP-induced Smad1 phosphorylation, blocking
ligand-dependent nuclear translocation of Smad1. These
studies define a new mode of regulation for intracellular BMP/Smad1 signaling.
*
This work was supported in part by grants from The Center
for Research in FOP and Related Disorders and the American Cancer Society and by Grant AR45587 from the National Institutes of Health (to
H. C. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
An Assistant Investigator of the Howard Hughes Medical Institute.
**
To whom correspondence should be addressed. Tel.: 215-898-2319;
Fax: 215-573-4320; E-mail: hchuang@mail.med.upenn.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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