Abstract
Cells continually sense and respond to cues in their environment. Many of these cues are transmitted through ligand–receptor interactions that activate intracellular signaling pathways and alter gene expression. Among the most important of these pathways is TGFβ signaling, which regulates processes including development, tissue homeostasis, wound healing, metabolism, and immune responses. Rather than operating as a linear pathway, TGFβ signaling emerges from a competitive interaction network whose output depends on the relative abundance of many interacting components. An additional layer of regulation is provided by coreceptors, which bind ligands and interact with signaling receptors but do not themselves directly transduce signal. Although coreceptors do not directly propagate intracellular signal, they are often abundantly expressed, and their loss can profoundly disrupt normal physiology, contributing to developmental defects and disease. Despite their biological importance, it remains difficult to predict how coreceptors shape signaling output within complex, multi-ligand environments.
In this dissertation, I combine computational modeling with single-cell in vitro measurements to define how coreceptors regulate TGFβ pathway activity. I identify a mechanistic basis for coreceptor-mediated inhibition and show that, in multi-ligand systems, coreceptors reshape competition among pathway components to alter the signaling landscape. I further find that coreceptors are among the most variably expressed components of the TGFβ pathway, suggesting that cells may tune signaling state by modulating coreceptor abundance. Together, these findings establish coreceptors as critical regulators of context-dependent TGFβ signaling and reveal how non-signaling pathway components can exert powerful control over cellular information processing.
