Wang Lin, Liu Zhiyu, Shi Herong, Liu Jun
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.
PLoS Genet. 2017 Jan 9;13(1):e1006568. doi: 10.1371/journal.pgen.1006568. eCollection 2017 Jan.
The highly conserved bone morphogenetic protein (BMP) signaling pathway regulates many developmental and homeostatic processes. While the core components of the BMP pathway have been well studied, much research is needed for understanding the mechanisms involved in the precise spatiotemporal control of BMP signaling in vivo. Here, we provide evidence that two paralogous and evolutionarily conserved tetraspanins, TSP-12 and TSP-14, function redundantly to promote BMP signaling in C. elegans. We further show that the ADAM10 (a disintegrin and metalloprotease 10) ortholog SUP-17 also functions to promote BMP signaling, and that TSP-12 can bind to and promote the cell surface localization of SUP-17. SUP-17/ADAM10 is known to be involved in the ligand-induced proteolytic processing of the Notch receptor. We have evidence that the function of SUP-17, and of TSP-12/TSP-14 in BMP signaling is independent of their roles in Notch signaling. Furthermore, presenilins, core components of the γ-secretase complex involved in processing Notch, do not appear to play a role in BMP signaling. These studies established a new role of the TSP-12/TSP-14/SUP-17 axis in regulating BMP signaling, in addition to their known function in the Notch signaling pathway. We also provide genetic evidence showing that a known BMP signaling modulator, UNC-40/neogenin/DCC, is one of the substrates of SUP-17/ADAM10 in the BMP signaling pathway.
高度保守的骨形态发生蛋白（BMP）信号通路调控着许多发育和稳态过程。虽然BMP通路的核心成分已得到充分研究，但要了解体内BMP信号精确的时空控制机制仍需大量研究。在此，我们提供证据表明，两个旁系同源且进化保守的四跨膜蛋白TSP - 12和TSP - 14在秀丽隐杆线虫中发挥冗余功能以促进BMP信号传导。我们进一步表明，ADAM10（一种解整合素和金属蛋白酶10）的直系同源物SUP - 17也具有促进BMP信号传导的功能，并且TSP - 12可以结合并促进SUP - 17在细胞表面的定位。已知SUP - 17/ADAM10参与Notch受体的配体诱导蛋白水解加工。我们有证据表明，SUP - 17以及TSP - 12/TSP - 14在BMP信号传导中的功能独立于它们在Notch信号传导中的作用。此外，早老素是参与Notch加工的γ-分泌酶复合物的核心成分，似乎在BMP信号传导中不起作用。这些研究确立了TSP - 12/TSP - 14/SUP - 17轴在调控BMP信号传导中的新作用，除了它们在Notch信号通路中的已知功能。我们还提供了遗传学证据，表明一种已知的BMP信号调节剂UNC - 40/新基因/DCC是BMP信号通路中SUP - 17/ADAM10的底物之一。
