title: Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids.
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.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Herong
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Szymczak
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Taner
authors.initials: T
authors.lastname: Aydin
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
authors.forename: Sijung
authors.initials: S
authors.lastname: Yun
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Katharine
authors.initials: K
authors.lastname: Constas
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Arielle
authors.initials: A
authors.lastname: Schaeffer
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Sinthu
authors.initials: S
authors.lastname: Ranjan
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Saad
authors.initials: S
authors.lastname: Kubba
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Emad
authors.initials: E
authors.lastname: Alam
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Devin E
authors.initials: DE
authors.lastname: McMahon
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Jingpeng
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Neta
authors.initials: N
authors.lastname: Shwartz
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Plavskin
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Lindy
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Nimra Amir
authors.initials: NA
authors.lastname: Dad
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Sunny
authors.initials: S
authors.lastname: Sheth
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Nirav M
authors.initials: NM
authors.lastname: Amin
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zimmerman
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Schwarz
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
authors.forename: Harold
authors.initials: H
authors.lastname: Smith
authors.affiliation: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Krause
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005819:Genetic Markers; D006028:Glycosphingolipids / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D029742:Caenorhabditis elegans Proteins; D005819:Genetic Markers; D006028:Glycosphingolipids; C483687:Sma-9 protein, C elegans; D059470:Tetraspanins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C500304:tsp-15 protein, C elegans