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J. Biol. Chem. 278 (1): 428-437

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

SANE, a Novel LEM Domain Protein, Regulates Bone Morphogenetic Protein Signaling through Interaction with Smad1*

G. Praveen RajuDagger , Neviana Dimova§, Peter S. KleinDagger §||, and Hui-Chuan Huang§**

From the Dagger  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-beta (TGF-beta ) 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-beta /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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF115498.

|| 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:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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