Professor of Pharmacology
Ph.D., University of California, San Diego
Key Words: proteases, G protein-coupled receptors, signal transduction, membrane trafficking, ubiquitination, inflammation, endothelial cells, breast cancer
The focus of our research is on protease signaling in vascular cells and cancer progression. Endothelial cells line blood vessels and form a semi-permeable barrier. During vascular injury and inflammation breakdown of the endothelial barrier occurs. We are examining how activation of GPCRs by distinct proteases differentially regulates endothelial barrier permeability through selective activation of signaling pathways. The capacity of distinct ligands to elicit unique signaling responses through activation of the same receptor is a phenomenon termed biased agonism. The mechanisms that control PAR biased signaling in endothelial cells and other cell types is not known and is a focus of our research. PARs are a family of GPCRs that are uniquely activated by proteolysis. Due to the unusual irreversible proteolytic mechanism of activation, endocytic trafficking is critical for controlling the fidelity of PAR signaling. We have discovered a novel ubiquitin-independent sorting pathway that regulates PAR1 trafficking from endosomes to lysosomes. We are currently examining how the function of this unique endocytic sorting machinery is regulated. We also discovered that PAR1 trafficking is dysregulated in invasive breast cancer and consequently the receptor signals persistently and transactivates EGFR and ErbB2 to promote tumor cell invasion and metastasis. The molecular mechanism responsible for dysregulated PAR1 trafficking in invasive breast cancer is not known and currently being investigated. We are examining how signaling by PAR is regulated by post-translational modifications and dimerization with other PARs at the cell surface and on endosomes and the impact on cellular behaviors. We use biochemical, cell biology and molecular biological approaches including BRET, TIRF and confocal imaging as well as siRNA library screens.
Selected Publications | PubMed Listing
U.J.K. Soh and J. Trejo. (2011) Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through beta-arrestins and dishevelled-2 scaffolds. Proc. Natl. Acad. Sci. USA.108: E1372-E1380
M.R. Dores, B. Chen, H. Lin, U.J.K. Soh, M.M. Paing, W. A. Montagne, T. Meerloo and J. Trejo. (2012) ALIX binds a YPX3L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting. J. Cell Biol. 197: 407-419
H. Lin and J. Trejo. (2013) Transactivation of the PAR1-PAR2 heterodimer by thrombin elicits beta-arrestin-mediated endosomal signaling. J. Biol. Chem. 288:11203-1121