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The context-dependent, combinatorial logic of BMP signaling

View ORCID ProfileHeidi Klumpe, View ORCID ProfileMatthew A. Langley, James M. Linton, View ORCID ProfileChristina J. Su, View ORCID ProfileYaron E. Antebi, View ORCID ProfileMichael B. Elowitz
doi: https://doi.org/10.1101/2020.12.08.416503
Heidi Klumpe
1Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA
2Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA
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Matthew A. Langley
1Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA
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James M. Linton
1Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA
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Christina J. Su
1Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA
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Yaron E. Antebi
3Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
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  • For correspondence: ayaron@weizmann.ac.il melowitz@caltech.edu
Michael B. Elowitz
1Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA 91125, USA
4Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
5Department of Applied Physics, California Institute of Technology, Pasadena, CA 91125, USA
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  • For correspondence: ayaron@weizmann.ac.il melowitz@caltech.edu
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Summary

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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://doi.org/10.22002/D1.1693

Copyright 
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.
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Posted December 08, 2020.
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The context-dependent, combinatorial logic of BMP signaling
Heidi 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
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The context-dependent, combinatorial logic of BMP signaling
Heidi 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

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