Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Dixit, Purushottam

Abstract

Ligands may carry information through features such as their concentration, identity, and spatial distribution. Cells that can resolve these properties gain access to additional dimensions of information which may be beneficial as certain ligand properties possess unique features (e.g., ligand identity does not disperse with distance the way concentration does). Cells can accomplish this, at least in part, through the use of signaling cascades initiated by membrane receptors which bind to the ligand and activate downstream processes. The properties of these signaling cascades depend on the "state" of the cell (a property encompassing important cell features like protein levels and mRNA abundances) which varies within a population. Here we examine how specific cell state features impact the ability of the cell to detect and process the information carried by ligands. We develop a novel information theory framework to quantify the distribution of signaling performances arising from differences in cell states within a population. Using this approach to probe multiple mammalian signaling cascades, we find receptors are capable of encoding significant amounts of information about external ligand levels (e.g., often greater than 3 bits for MCF10A cells). After establishing the ability of the receptor to reliably detect external ligand concentrations, we next explore how these receptors might identify other important ligand properties. We find receptors are able to tune their activity to selectively respond to specific ligand identities using a kinetic proofreading like mechanism (which we call "kinetic sorting"). Additionally, we propose a novel mechanism for directional chemosensing which occurs entirely through receptor-level processes such as diffusion and the preferential degradation of active receptors. This work highlights the often unappreciated role of receptors as processing hubs of information rather than just a means to make ligand-level information available to downstream processes.

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