Ligand-receptor promiscuity enables cellular addressing

Abstract

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.

Programmable protein circuit design

“…Fourth, most of the circuits discussed here build upon specific one-to-one protein-protein interactions. However, natural eukaryotic signaling systems often comprise sets of promiscuously interacting proteins that, together, can perform complex computations through mechanisms loosely analogous to neural networks (Su et al, 2020). The ability to rationally design similar promiscuous network architectures could lead to distinct paradigms for biochemical computation that exceed the capabilities of simpler Boolean logic.…”

“…However, natural (especially mammalian) sensing systems appear to use promiscuous (many-to-many) interactions between sets of ligand and receptor variants to selectively respond to complex combinations of their inputs (Antebi et al, 2017). Computational approaches indicate that competition to form a variety of protein complexes with different activities can perform complex signal processing operations (Su et al, 2020). It will be interesting to see whether these principles can be adapted to enable synthetic circuits with similar functions.…”

Combinatorial expression motifs in signaling pathways

“…One appealing possibility is that each motif has a distinct but related signaling function that is retained in some way even in different cell types or contexts. For example, in a "combinatorial addressing" system, different ligand combinations could selectively activate sets of cell types based on their receptor expression profiles, to achieve greater cell type specificity in signaling (Klumpe et al, 2020;Su et al, 2020). A similar principle could apply to juxtacrine signaling pathways such as Notch and Eph-ephrin, where the combination of components expressed in a given cell type could control which other cell types it can communicate with, based on their own pathway expression profiles.…”

“…However, examining pathway expression patterns globally, as we did here, reveals a more subtle situation, in which pathways can be expressed in a finite number of distinct configurations, characterized by different expression levels for its components, all potentially competent to signal in response to suitable inputs. Each configuration could be functional in some contexts but nevertheless differ from other configurations in the specific input ligands it senses, or the downstream effectors it activates within the cell (Antebi, Nandagopal, et al, 2017;Buckles et al, 2004;Klumpe et al, 2020;LeBon et al, 2014;Li & Elowitz, 2019;Rohani et al, 2014;Su et al, 2020;Verkaar & Zaman, 2010).…”

Single cell biology—a Keystone Symposia report

“…1 Elowitz expects that MultiFate will provide a core capability necessary for synthetic multicellular organisms. His lab is also working on other features of organisms, such as intercellular signaling 2 and cell population control, to build such a synthetic system. 3…”