Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of ligands. Malfunction of the pathway in humans can cause various developmental or physiological disorders. Thus it is critical that the BMP pathway is tightly regulated. Our lab has developed a sensitive and specific genetic screen in C. elegans to identify novel components that function to modulate BMP signaling (Liu et al., 2015). Using this screen, we have recently identified two evolutionarily conserved tetraspanins, TSP-12 and TSP-14, and an ADAM (a disintegrin and metalloprotease) protease SUP-17, that function in promoting BMP signaling. TSP-12 and TSP-14 are paralogs that belong to the TspanC8 subfamily of tetraspanins, while SUP-17 is the ortholog of ADAM10. We have found that TSP-12 and TSP-14 function redundantly through SUP-17 to promote BMP signaling. All three proteins are expressed, and function, in the BMP receptor-expressing cells to modulate pathway activity. Both TSP-12 and TSP-14 can bind SUP-17 in a membrane-based yeast two-hybrid system, and are required for the cell surface localization of SUP-17. SUP-17/ADAM10 is known to cleave cell surface proteins through a process called ‘ectodomain shedding’. One of the best known substrates of SUP-17/ADAM10 is Notch. We have found that the function of TSP-12, TSP-14 and SUP-17 in BMP signaling is independent of Notch signaling. We further provide genetic evidence that the neogenin homolog UNC-40, another positive modulator of BMP signaling (Tian et al., 2013), is one substrate of SUP-17/ADAM10. TSP-12, TSP-14, SUP-17 and UNC-40 are all conserved in mammals. We are currently determining whether their roles in BMP signaling are also conserved in mammals.
*The first two authors contributed equally to this work.
References:
Liu et al,. Promotion of bone morphogenetic protein signaling by tetraspanins and glycosphingolipids. PLoS Genetics. 2015 May 15;11(5):e1005221. doi: 10.1371/journal.pgen.1005221. eCollection 2015.
Tian et al., The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans. Development. 2013 Oct;140(19):4070-80. doi: 10.1242/dev.099838. Epub 2013 Sep 4.