Promotion of Bone Morphogenetic Protein Signaling by Tetraspanins and Glycosphingolipids

Autor: Katharine Constas, Devin E. McMahon, Dennis Liu, Michael W. Krause, Harold E. Smith, Nirav M. Amin, Emad Alam, Sinthu Ranjan, Chenxi Tian, Erich M. Schwarz, Neta Shwartz, Zhiyu Liu, Lindsey C. Szymczak, Sijung Yun, Arielle Schaeffer, Amanda S. Lindy, Herong Shi, Sunny Sheth, Jingpeng He, Saad Kubba, Jun Liu, Nimra Amir Dad, Stephanie Zimmerman, Taner Aydin, Yevgeniy Plavskin
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Genetic Markers
Cancer Research
endocrine system
lcsh:QH426-470
Tetraspanins
Molecular Sequence Data
Notch signaling pathway
Biology
Bone morphogenetic protein
Sensitivity and Specificity
Glycosphingolipids
03 medical and health sciences
0302 clinical medicine
Tetraspanin
immune system diseases
Genes
Reporter
Transforming Growth Factor beta
Genetics
Animals
Amino Acid Sequence
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Molecular Biology
Transcription factor
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
0303 health sciences
virus diseases
Transforming growth factor beta
Sequence Analysis
DNA
3. Good health
BMPR2
Cell biology
lcsh:Genetics
Phenotype
Gene Expression Regulation
030220 oncology & carcinogenesis
embryonic structures
Bone Morphogenetic Proteins
Mutation
biology.protein
Signal transduction
Transforming growth factor
Research Article
Signal Transduction
Transcription Factors
Zdroj: PLoS Genetics
PLoS Genetics, Vol 11, Iss 5, p e1005221 (2015)
ISSN: 1553-7404
1553-7390
Popis: 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.
Author Summary The bone morphogenetic protein (BMP) signaling pathway is required for multiple developmental processes during metazoan development. Various diseases, including cancer, can result from mis-regulation of the BMP pathway. Thus, it is critical to identify factors that ensure proper regulation of BMP signaling. Using the nematode C. elegans, we have devised a highly specific and sensitive genetic screen to identify new modulators in the BMP pathway. Through this screen, we identified three conserved tetraspanin molecules as novel factors that function to promote BMP signaling in a living organism. We further showed that these three tetraspanins likely form a complex and function together with glycosphingolipids to promote BMP signaling. Recent studies have implicated several tetraspanins in cancer initiation, progression and metastasis in mammals. Our findings suggest that the involvement of tetraspanins in cancer may partially be due to their function in modulating the activity of BMP signaling.
Databáze: OpenAIRE
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