Combinatorial Signal Perception in the BMP Pathway
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.
© 2017 Elsevier Inc. Received 4 October 2016, Revised 26 April 2017, Accepted 8 August 2017, Available online 7 September 2017. We thank Uri Alon, James Briscoe, Marcelo Ehrlich, Jordi Garcia-Ojalvo, Lea Goentoro, Roy Kishony, Vicki Rosen, Boris Shraiman, Ned Wingreen, and members of the Elowitz lab for helpful discussions and feedback. We thank the Caltech Flow Cytometry Facility and the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech for technical assistance. This work was supported by the Gordon and Betty Moore Foundation (grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative), the Human Frontiers Science Program (grant RGP0020), the NIH (grant R01 HD75335A), the Defense Advanced Research Projects Agency (contract HR0011-16-0138), and the Institute for Collaborative Biotechnologies (grant W911NF-09-0001 from the US Army Research Office). This work does not necessarily reflect the position or policy of the US Government, and no official endorsement should be inferred. H.K. is supported by a National Science Foundation graduate research fellowship (grant DGE-1144469). C.S. is supported by the NIH (National Institute of General Medical Sciences training grant T32 GM008042) and by a David Geffen Medical Scholarship. Y.E.A., J.M.L., and M.B.E. filed a provisional patent application relating to this work.
Supplemental Material - mmc1.pdf
Accepted Version - nihms900407.pdf