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SANE, a Novel LEM Domain Protein, Regulates Bone Morphogenetic
Protein Signaling through Interaction with Smad1*
G. Praveen
Raju,
Neviana
Dimova§,
Peter S.
Klein§¶, and
Hui-Chuan
Huang§**
From the Cell & Molecular Biology Graduate Group, the
§ Department of Medicine, and the ¶ Howard Hughes
Medical Institute, the University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104
Bone morphogenetic proteins (BMPs) are members of
the transforming growth factor- (TGF-) superfamily that play
importantroles in bone formation, embryonic patterning, and
epidermal-neuralcell fate decisions. BMPs signal through pathway
specific mediatorssuch as Smads1 and 5, but the upstream regulation of
BMP-specificSmads has not been fully characterized. Here we report the
identificationof SANE (Smad1 Antagonistic
Effector), a novel protein with significantsequence
similarity to nuclear envelop proteins such as MAN1.SANE binds to
Smad1/5 and to BMP type I receptors and regulatesBMP signaling. SANE
specifically blocks BMP-dependent signalingin
Xenopus embryos and in a mammalian model of bone formationbut does not inhibit the TGF-/Smad2 pathway. Inhibition of BMPsignaling by SANE requires interaction between SANE and Smad1,because
a SANE mutant that does not bind Smad1 does not inhibitBMP signaling.
Furthermore, inhibition appears to be mediatedby inhibition of
BMP-induced Smad1 phosphorylation, blocking
ligand-dependentnuclear translocation of Smad1. These
studies define a new modeof regulation for intracellular BMP/Smad1signaling.
*
This work was supported in part by grants from The Center
for Research in FOP and Related Disorders and the American CancerSociety and by Grant AR45587 from the National Institutes of Health(to
H. C. H.).The costs of publication of this
article were defrayedin part by the
payment of page charges. The article
must thereforebe hereby marked
"advertisement" in
accordance with 18 U.S.C.Section
1734 solely to indicate thisfact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s)AF115498.
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