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The context-dependent, combinatorial logic of BMP signaling

Klumpe, Heidi and Langley, Matthew A. and Linton, James M. and Su, Christina J. and Antebi, Yaron E. and Elowitz, Michael B. (2020) The context-dependent, combinatorial logic of BMP signaling. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20201210-094756085

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Abstract

Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends in a complex way on which ligands are present and what 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 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.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2020.12.08.416503DOIDiscussion Paper
https://doi.org/10.22002/D1.1693DOIData/Code
ORCID:
AuthorORCID
Klumpe, Heidi0000-0001-8938-2006
Langley, Matthew A.0000-0003-2890-5584
Su, Christina J.0000-0002-9223-9777
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 8, 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. H.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. M.B.E. is a Howard Hughes Medical Institute Investigator. Author Contributions: H.K., Y.E.A., and M.B.E. conceived and designed the experiments. H.K., M.A.L., and J.M.L. performed the experiments. H.K. and M.A.L. analyzed the experimental data. H.K., Y.E.A., and C.J.S. developed and fit the model. H.K., Y.E.A., and M.B.E wrote the paper. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)HR0011-16-0138
Gordon and Betty Moore FoundationGBMF2809
Human Frontier Science ProgramRGP0020
Army Research Office (ARO)W911NF-09-0001
NIHR01 HD075335A
NIHR01 MH116508
Paul G. Allen Frontiers GroupUWSC10142
NSF Graduate Research FellowshipDGE-1144469
NIH Predoctoral FellowshipT32 GM008042
David Geffen Medical ScholarshipUNSPECIFIED
Natural Sciences and Engineering Research Council of Canada (NSERC)UNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:bone morphogenetic protein, BMP, signaling pathways, cell context, combinatorial signaling, promiscuous receptor-ligand interactions, pairwise interaction analysis
Record Number:CaltechAUTHORS:20201210-094756085
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201210-094756085
Official Citation:The context-dependent, combinatorial logic of BMP signaling. Heidi E Klumpe, Matthew A Langley, James M Linton, Christina J Su, Yaron E Antebi, Michael B Elowitz. bioRxiv 2020.12.08.416503; doi: https://doi.org/10.1101/2020.12.08.416503
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107007
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Dec 2020 18:27
Last Modified:10 Dec 2020 18:27

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