Research
How is signaling organized in a living cell?
Nearly every biological process depends on a cell’s ability to accurately detect and appropriately respond to cues from its environment and from other cells. While these cues are incredibly diverse, ranging from photons to chemicals to peptides and proteins, information processing within the cell is achieved using a limited number of common signal transduction pathways. How these processes are regulated in space and time to encode stimulus-specific responses remains poorly understood.
The overarching goal of our lab is to investigate how this biochemical organization of the cell precisely regulates signal transduction. Our research focuses on signaling mediated by G protein-coupled receptors (GPCRs), the largest and most diverse family of transmembrane receptors. Upon activation at the plasma membrane, many GPCRs undergo endocytosis, and this trafficking has profound effects on downstream cellular responses. Using a combination of biochemistry, cell biology, and proteomics approaches, we aim to characterize the molecular mechanisms by which GPCRs and their associated proteins translocate during signaling and explore how this dynamic organization encodes the appropriate physiological responses to stimuli. In particular, we are interested in exploring three broad questions:
Where are proteins located during signaling?
GPCRs interact with scaffolding proteins to form macromolecular complexes with downstream effectors and regulatory proteins. Different complexes can be formed depending on the subcellular location. We are exploring how both of these aspects of "location" change during signal transduction, for GPCRs and for other key pathway proteins.
What are the mechanisms of protein translocation?
We aim to gain a mechanistic understanding of how GPCR activation leads to the subcellular translocation of target proteins. To begin, we are focusing on understanding how the internalization of receptor itself is regulated in diverse ways. In the canonical pathway of GPCR endocytosis, ligand binding leads to receptor phosphorylation, which then recruits an endocytic adaptor protein called β-arrestin. However, we and others have demonstrated that not all GPCRs require β-arrestin for endocytosis. In these cases, what endocytic adaptors mediate receptor internalization, and how is this interaction regulated by ligand?
Related publication: Blythe & von Zastrow 2024 (PMID: 37749347).
Why does location matter?
Ongoing work endeavors to address this question by measuring the effects of perturbing protein translocation on downstream signaling in live cells using biosensors. By comparing GPCRs that utilize distinct trafficking itineraries, we hope to gain insight into the molecular logic linking receptor localization to signal transduction.