Summary The Bone Morphogenetic Protein (BMP) signaling pathway comprises multiple ligands and receptors that interact promiscuously with one another, and typically appear in combinations. This feature is often explained in terms of redundancy and regulatory flexibility, but it has remained unclear what signal processing capabilities it provides. Here, we show that the BMP pathway processes multi-ligand inputs using a specific repertoire of computations, including ratiometric sensing, balance detection and imbalance detection. These computations operate on the relative levels of different ligands, and can arise directly from competitive receptor-ligand interactions. Furthermore, cells can select different computations to perform on the same ligand combination through expression of alternative sets of receptor variants. These results provide a direct signal processing role for promiscuous receptor-ligand interactions, and establish operational principles for quantitatively controlling cells with BMP ligands. Similar principles could apply to other promiscuous signaling pathways.

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AFF patients experienced delayed healing, prodromal pain, and persisting risk of a contralateral and/or other fracture. Femur pain evaluation in patients on long-term bisphosphonates may facilitate early diagnosis of stress AFFs, permitting intervention, thus reducing completed and/or contralateral or other fracture risk. The details of these histories will assist in counseling regarding prognosis after an initial AFF.

In multicellular organisms, secreted ligands selectively activate, or “address,” specific target cell populations to control cell fate decision-making and other processes. Key cell-cell communication pathways use multiple promiscuously interacting ligands and receptors, provoking the question of how addressing specificity can emerge from molecular promiscuity. To investigate this issue, we developed a general mathematical modeling framework based on the bone morphogenetic protein (BMP) pathway architecture. We find that promiscuously interacting ligand-receptor systems allow a small number of ligands, acting in combinations, to address a larger number of individual cell types, each defined by its receptor expression profile. Promiscuous systems outperform seemingly more specific one-to-one signaling architectures in addressing capacity. Combinatorial addressing extends to groups of cell types, is robust to receptor expression noise, grows more powerful with increasing receptor multiplicity, and is maximized by specific biochemical parameter relationships. Together, these results identify fundamental design principles governing cell addressing by ligand combinations.