Sarah Shelby Assistant Professor, BCMB
Ph.D. Biophysics, Cornell University
Signaling processes on the plasma membrane shape the way that cells sense and respond to stimuli, determining cellular decisions to activate, migrate, proliferate, etc. Engagement of antigens by cell surface immune receptors, for example, can lead to cellular activation and downstream immune effector responses. This finely tuned and tightly regulated signaling cascade originates in the plasma membrane, where receptors reorganize to form new interactions with signaling partners to transduce the activation signal. The plasma membrane itself is a complex mixture of proteins and lipids with a heterogeneous and dynamic structure. As a result, receptors and signaling molecules encounter various kinds of membrane microenvironments that can organize, compartmentalize, or locally regulate the biochemical steps of signaling.
We are interested in how the structure and organization of the mammalian plasma membrane regulates signaling pathways in time and space, with a focus on immune receptor signaling in T cells. In addition to native T cell receptors (TCRs), we use receptors engineered for immunotherapy known as chimeric antigen receptors (CARs) as a model to study spatial regulation of immune signaling. Super-resolution fluorescence microscopy is our main experimental tool to approach these questions. Live cell super-resolution imaging experiments can directly probe co-localization and dynamics of membrane components to tease apart interactions that control biochemical signaling cascades. From this foundation, we aim to:
· Identify structure-function relationships between TCR/CAR receptor organization and signaling.
· Investigate how membrane physical properties and interactions (e.g. membrane-cytoskeleton contacts, lipid domains, etc.) create environments that influence TCR/CAR signaling.
· Develop new super-resolution probes and imaging modalities to access spatial information about signaling activity (e.g. kinase activity, phosphorylation) and function.
Shelby, S. A., Castello-Serrano, I., Wisser, K., Levental, I., & Veatch, S. (2023). Membrane phase separation drives responsive assembly of receptor signaling domains. Nature Chemical Biology. 1–9. https://doi.org/10.1038/s41589-023-01268-8
Shelby, S. A., Shaw, T. R., & Veatch, S. L. (2023). Measuring the co-localization and dynamics of mobile proteins in live cells undergoing signaling responses. In C. T. Baldari & M. L. Dustin (Eds.), The Immune Synapse: Methods and Protocols (2nd ed., Vol. 2654). Humana. Preprint on bioRxiv (p. 2022.10.17.511423). https://doi.org/10.1101/2022.10.17.511423
Veatch, S. L.*, Rogers, N., Decker, A., & Shelby, S. A*. (2022). The plasma membrane as an adaptable fluid mosaic. Biochimica et Biophysica Acta (BBA)-Biomembranes, 184114. https://doi.org/10.1016/j.bbamem.2022.184114
Stone, M. B.*, Shelby, S. A.*, Núñez, M. F., Wisser, K., & Veatch, S. L. (2017). Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes. ELife, 6. https://doi.org/10.7554/eLife.19891
*authors contributed equally
Shelby, S. A., Veatch, S. L., Holowka, D. A., & Baird, B. A. (2016). Functional nanoscale coupling of Lyn kinase with IgE-FcεRI is restricted by the actin cytoskeleton in early antigen-stimulated signaling. Molecular Biology of the Cell, 27(22), 3645–3658. https://doi.org/10.1091/mbc.E16-06-0425
Shelby, S. A., Holowka, D., Baird, B., & Veatch, S. L. (2013). Distinct Stages of Stimulated FcεRI Receptor Clustering and Immobilization Are Identified through
Superresolution Imaging. Biophysical Journal, 105(10), 2343–2354. https://doi.org/10.1016/j.bpj.2013.09.049