Lecturer: Yaron E Antebi
Abstract:
The bone morphogenetic protein (BMP) signaling pathway plays key roles in diverse developmental processes. A striking feature of the pathway is its simultaneous and overlapping use of multiple receptor and ligand variants. These variants can interact with one another promiscuously to potentially generate a combinatorial set of hundreds of distinct complexes, all phosphorylating the same downstream targets. The use of many, seemingly redundant, variant complexes has been suggested to provide redundancy or regulatory flexibility. However, it has remained unclear whether it could enable additional signal processing capabilities. To understand how ligands are combined, we used quantitative experimental analysis of BMP signaling together with mathematical modeling. Experiments revealed that the BMP pathway integrates multiple ligands using a specific repertoire of computations. These computations generally depend on the relative, rather than absolute, levels of different ligands, and can arise directly from receptor-ligand interactions without requiring transcriptional regulation or feedback loops. Furthermore, the specific computation a cell performs depends on its receptor expression profile, allowing different cell types to perceive distinct combinations of ligands in the same environment. These results can explain the pathway response in several biological processes and should enable predictive understanding and control of BMP signaling in biomedical contexts. Moreover this can help explain the prevalence of promiscuous ligand-receptor architectures in developmental signaling pathways.