Liu Zhiyu, Shi Herong, Szymczak Lindsey C, Aydin Taner, Yun Sijung, Constas Katharine, Schaeffer Arielle, Ranjan Sinthu, Kubba Saad, Alam Emad, McMahon Devin E, He Jingpeng, Shwartz Neta, Tian Chenxi, Plavskin Yevgeniy, Lindy Amanda, Dad Nimra Amir, Sheth Sunny, Amin Nirav M, Zimmerman Stephanie, Liu Dennis, Schwarz Erich M, Smith Harold, Krause Michael W, Liu Jun
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America.
PLoS Genet. 2015 May 15;11(5):e1005221. doi: 10.1371/journal.pgen.1005221. eCollection 2015 May.
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.
骨形态发生蛋白（BMPs）属于分泌分子的转化生长因子β（TGFβ）超家族。BMPs在多细胞动物的多个发育和稳态过程中发挥着重要作用。BMP信号通路功能异常可导致人类多种疾病，包括癌症、骨骼疾病和心血管疾病。确定确保BMP信号在时空上得到适当控制的因素对于理解该信号通路的调控机制至关重要。我们利用一种独特且灵敏的遗传筛选方法，鉴定出质膜定位的四跨膜蛋白TSP - 21是秀丽隐杆线虫中控制体型和胚胎后M系发育的类BMP“ Sma / Mab”信号通路中的一个关键新因子。我们发现TSP - 21在信号接收细胞中起作用，并且在配体 - 受体水平上发挥遗传功能。我们进一步表明，TSP - 21可以与自身以及另外两种四跨膜蛋白TSP - 12和TSP - 14相互作用，这两种蛋白也能促进Sma / Mab信号传导。TSP - 12和TSP - 14还可以与Sma / Mab通路的I型受体SMA - 6相互作用。最后，我们发现糖鞘脂是富含四跨膜蛋白的微结构域的主要成分，是Sma / Mab信号传导所必需的。我们的研究结果表明，富含四跨膜蛋白的膜微结构域对于BMP信号的正常传导很重要。由于四跨膜蛋白已成为肿瘤进展的诊断和预后标志物，并且TSP - 21、TSP - 12和TSP - 14在人类中均保守存在，我们推测某些四跨膜蛋白的表达或功能改变导致的BMP信号异常可能是癌症发生的一个促成因素。
