The context-dependent, combinatorial logic of BMP signaling
Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way in which ligands are presented extracellularly and receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise bone morphogenetic protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on the competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems.
Additional Information© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 5 December 2020, Revised 23 March 2021, Accepted 18 March 2022, Available online 13 April 2022. This work was supported by the Defense Advanced Research Projects Agency (contract HR0011-16-0138), the Gordon and Betty Moore Foundation (grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative), the Human Frontiers Science Program (grant RGP0020), the Institute for Collaborative Biotechnologies (grant W911NF-09-0001 from the U.S. Army Research Office), the National Institutes of Health (NIH) (grants R01 HD075335A and R01 MH116508), and the Paul G. Allen Frontiers Group and Prime Awarding Agency (award UWSC10142). This work does not necessarily reflect the position or policy of the U.S. Government, and no official endorsement should be inferred. H.E.K. is supported by a National Science Foundation graduate research fellowship (grant DGE-1144469). C.J.S. is supported by the NIH National Institute of General Medical Sciences (grant T32 GM008042) and a David Geffen Medical Scholarship. M.A.L. is supported by the National Sciences and Engineering Research Council of Canada Postgraduate Doctoral Scholarship. Y.E.A is supported by the Israel Science Foundation (grant 1105/20) and is the incumbent Sygnet Career Development Chair for Bioinformatics. M.B.E. is a Howard Hughes Medical Institute investigator. Author contributions: H.E.K., Y.E.A., and M.B.E. conceived and designed the experiments. H.E.K., M.A.L., and J.M.L. performed the experiments. H.E.K. and M.A.L. analyzed the experimental data. H.E.K., Y.E.A., and C.J.S. developed and fit the model. H.E.K., Y.E.A., and M.B.E. wrote the paper. Declaration of interests: The authors have one patent related to this work, US patent number 10,527,631. H.E.K. is currently a postdoctoral researcher at the Department of Biomedical Engineering at Boston University. C.J.S. is currently a medical student at the University of Illinois, Chicago. Data and code availability: Source data statement: Flow cytometry and qPCR data have been deposited at Caltech DATA and are publicly available as of the date of publication. DOIs are listed in the key resources table. This paper also analyzes existing, publicly available data. The accession numbers for these datasets are also listed in the key resources table. Code statement: All original code has been deposited at Caltech DATA and is publicly available as of the date of publication. DOIs are listed in the key resources table. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Published - 1-s2.0-S2405471222001296-main.pdf
Submitted - 2020.12.08.416503v1.full.pdf
Supplemental Material - 1-s2.0-S2405471222001296-mmc1.pdf
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