SANE, a novel LEM domain protein, regulates bone morphogenetic protein signaling through interaction with Smad1.
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.
Raju
G Praveen
GP
Cell & Molecular Biology Graduate Group, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Dimova
Neviana
N
Klein
Peter S
PS
Huang
Hui-Chuan
HC
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D019521:Body Patterning; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000033:anatomy & histology / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D009865:Oocytes / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016378:Tissue Transplantation; D015534:Trans-Activators / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D014981:Xenopus / Q000502:physiology; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C485769:LEMD3 protein, Xenopus; C405329:LEMD3 protein, human; C497402:MXD1 protein, Xenopus; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C470846:SANE protein, Xenopus; C497399:SMAD1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D020825:T-Box Domain Proteins; C116765:TBXT protein, Xenopus; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I