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Ligand-receptor promiscuity enables cellular addressing

Su, Christina J. and Murugan, Arvind and Linton, James M. and Yeluri, Akshay and Bois, Justin and Klumpe, Heidi and Antebi, Yaron E. and Elowitz, Michael B. (2020) Ligand-receptor promiscuity enables cellular addressing. . (Unpublished)

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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.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Su, Christina J.0000-0002-9223-9777
Murugan, Arvind0000-0001-5464-917X
Yeluri, Akshay0000-0001-8654-1673
Bois, Justin0000-0001-7137-8746
Klumpe, Heidi0000-0001-8938-2006
Antebi, Yaron E.0000-0002-5771-6814
Elowitz, Michael B.0000-0002-1221-0967
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. This version posted December 9, 2020. 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. C.J.S. is supported by the NIH National Institute of General Medical Sciences (grant T32 GM008042) and a David Geffen Medical Scholarship. H.K. is supported by a National Science Foundation graduate research fellowship (grant DGE-1144469). M.B.E. is a Howard Hughes Medical Institute Investigator. Author Contributions: C.J.S., A.M., Y.E.A., and M.B.E. conceived and designed the research. J.M.L., H.K., and Y.E.A. performed experiments. C.J.S., A.M., A.Y., J.B., and Y.E.A. developed mathematical models and performed computational analysis. C.J.S., A.M., Y.E.A., and M.B.E. wrote the manuscript. The authors declare no competing interests.
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)HR0011-16-0138
Gordon and Betty Moore FoundationGBMF2809
Caltech Programmable Molecular Technology InitiativeUNSPECIFIED
Human Frontier Science ProgramRGP0020
Army Research Office (ARO)W911NF-09-0001
NIHR01 HD075335A
NIHR01 MH116508
Paul G. Allen Frontiers GroupUWSC10142
NIH Predoctoral FellowshipT32 GM008042
David Geffen Medical ScholarshipUNSPECIFIED
NSF Graduate Research FellowshipDGE-1144469
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:bone morphogenetic protein, BMP, signaling pathways, promiscuity, multiplicity, ligand-receptor interactions, communication systems, signal processing, information theory, cell type specificity
Record Number:CaltechAUTHORS:20201210-134335099
Persistent URL:
Official Citation:Ligand-receptor promiscuity enables cellular addressing. Christina J. Su, Arvind Murugan, James M. Linton, Akshay Yeluri, Justin Bois, Heidi Klumpe, Yaron E. Antebi, Michael B. Elowitz. bioRxiv 2020.12.08.412643; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107015
Deposited By: Tony Diaz
Deposited On:10 Dec 2020 21:53
Last Modified:10 Dec 2020 21:53

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