DeGroot, Melisa S et al. (2021) MicroPubl Biol

DeGroot, Melisa S, Liu, Jun, Greer, Robert

[MicroPubl Biol, 2021]

Heparan sulfate proteoglycans (HSPGs) are macromolecules composed of a protein core decorated with glycosaminoglycan (GAG) chains. These highly diverse molecules are classified based on their localization at the membrane or being secreted as part of the extracellular matrix (ECM), such as glypicans or perlecans, respectively (Sarrazin et al. 2011). HSPGs have been shown to play a structural role in the ECM as well as in the distribution of growth factors, such as transforming growth factor- (TGF-), fibroblast growth factor (FGF), Wnt, and Hedgehog (Hh), within tissues through highly specific binding interactions (Lin and Perrimon 2000). In vitro studies have demonstrated that human perlecan can bind to the BMP2 ligand (Decarlo et al. 2012). Understanding the biological roles of HSPGs in cell signaling has implications in disease diagnosis and potential treatment.

DeGroot, Melisa et al. (2021) International Worm Meeting "The secreted modular calcium binding protein (SMOC-1) can function as both a long-range and a short-range modulator of BMP signaling in C. elegans"

Williams, Byron, Liu, Jun, DeGroot, Melisa

[International Worm Meeting, 2021]

The bone morphogenetic protein (BMP) pathway is a highly conserved signaling cascade that regulates key developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans SMOC-1 (secreted modular calcium-binding protein-1) protein as a positive modulator of the BMP pathway. SMOC-1 is a predicted secreted matricellular protein with two predicted functional domains: the thyroglobulin-like type I repeat (TY) domain and the extracellular calcium binding (EC domain). Through a series of molecular genetic experiments, we have demonstrated that SMOC-1 functions in a positive feedback loop to promote BMP signaling: it acts through the BMP ligand DBL-1 to regulate BMP signaling, and its expression in the intestine is positively regulated by BMP signaling. smoc-1 is expressed in multiple tissues. Using cell type specific promoters to drive smoc-1 expression, we found that SMOC-1 functions cell non-autonomously to regulate body size. Surprisingly, a membrane-tethered SMOC-1 driven by the smoc-1 promoter can also partially function. These findings suggest that SMOC-1 can act both locally and over a distance to regulate BMP signaling. Intriguingly, the SMOC-1 EC domain alone is sufficient to regulate the BMP pathway when freely secreted, but not when membrane tethered. Conversely, the TY domain alone is not sufficient to promote BMP signaling, yet this domain is required for SMOC-1 to function locally. Together, these findings suggest that the SMOC-1 TY and EC domains contribute to different facets of SMOC-1 functions. We are using immunoprecipation/mass spectrometry (IP/MS) to identify interacting partners of the various functional forms of SMOC-1. Comparative analysis of the IP/MS results will yield molecular insights on how SMOC-1 promotes the BMP pathway.