RRC ID 45596
Author Liu Z, Shi H, Szymczak LC, Aydin T, Yun S, Constas K, Schaeffer A, Ranjan S, Kubba S, Alam E, McMahon DE, He J, Shwartz N, Tian C, Plavskin Y, Lindy A, Dad NA, Sheth S, Amin NM, Zimmerman S, Liu D, Schwarz EM, Smith H, Krause MW, Liu J.
Title Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids.
Journal PLoS Genet
Abstract Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like "Sma/Mab" signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development.
Volume 11(5)
Pages e1005221
Published 2015-5
DOI 10.1371/journal.pgen.1005221
PII PGENETICS-D-14-03380
PMID 25978409
PMC PMC4433240
MeSH Amino Acid Sequence Animals Bone Morphogenetic Proteins / genetics Bone Morphogenetic Proteins / metabolism* Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Gene Expression Regulation Genes, Reporter Genetic Markers Glycosphingolipids / pharmacology* Molecular Sequence Data Mutation Phenotype Sensitivity and Specificity Sequence Analysis, DNA Signal Transduction* Tetraspanins / genetics Tetraspanins / metabolism* Transcription Factors / antagonists & inhibitors Transcription Factors / genetics Transcription Factors / metabolism Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism
IF 5.224
Times Cited 11
WOS Category GENETICS & HEREDITY
Resource
C.elegans tm6269 tm331 tm2218