Regulation of receptor signaling
A main focus of our research is to dissect how receptor function is regulated at the cellular and molecular levels. We recently discovered that cellular responses to GPCR signaling are spatially regulated. GPCRs were previously thought to signal exclusively from the surface by production of second messengers such as cyclic AMP (cAMP), and then to be turned “off” by delivery to endosomes (Figure, left). Using the prototypical GPCR, the beta2-adrenoceptor (β2-AR), we have shown that β2-AR/cAMP signaling from endosomes (and not the cell surface) drives the receptor-induced transcriptional response (Figure, right). This ability of cells to discriminate the subcellular location of cAMP production when initiating a functional response– which we call “spatial encoding” of signaling– represents a general paradigm for expanding the signaling capabilities of an individual pathway.
Figure- Spatial encoding of GPCR/cAMP cellular responses. Left, The classical GPCR model: receptors sense ligands and initiate signal transduction from the cell surface, but are turned “off” once internalized. Right, A revised model based on our data: GPCRs activation and cAMP production from endosomal receptors is more efficiently coupled to the cellular transcriptional response.
We are presently focusing on:
Identifying the molecular mechanisms controlling localized signaling: How does the cell respond differently to the same signal, when it comes from distinct sites?
Identifying and characterizing novel biochemical mechanisms regulating receptor function. We identify mechanisms through systematic mapping of changes in the cellular phosphorylation and gene expression landscapes and unbiased functional genomic screens. We then characterize candidate genes and pathways in the context of receptor function.
For reference, see:
Tsvetanova NG and von Zastrow M. (2014). Spatial encoding of cAMP signaling specificity by GPCR endocytosis. Nature Chemical Biology 10: 1061-1065.
Semesta KM, Tian R, Kampmann M, von Zastrow M, Tsvetanova NG. (2020). A high-throughput CRISPR interference screen for dissecting functional regulators of GPCR/cAMP signaling. PLoS Genetics 16(10): e1009103.
Willette BKA, Zhang JF, Zhang J and Tsvetanova NG. (2024). Endosome positioning coordinates spatially selective GPCR signaling. Nature Chemical Biology 20: 151-161.