JoAnn Trejo Associate Professor of Pharmacology Ph.D., University of California, San Diego Phone: 858-246-0150 Fax: 858-822-0041 E-mail: joanntrejo@ucsd.edu Lab Website

Key Words: protease-activated receptors, G-proteins, signal transduction, ubiquitination, endocytosis, membrane trafficking, sorting nexins, endothelial cells, breast cancer

The long-term goal of our research program is to fully understand the mechanisms by which extracellular proteases elicit cellular responses and contribute to vascular diseases and cancer progression. The focus of our work is on protease-activated receptors (PARs), which are G protein-coupled receptors (GPCRs) that transmit signals in response to coagulant proteases and other extracellular proteases. PARs play crucial roles in hemostasis and thrombosis, as well as in inflammatory and proliferative responses triggered by vascular injury. PARs are also important for vascular development and tumor progression. PARs are activated by a unique irreversible proteolytic mechanism and therefore signaling must be tightly regulated. Desensitization and trafficking of proteolytically activated PARs control the magnitude, duration and spatial aspects of receptor signaling. We study novel ubiquitin-dependent processes that regulate PAR endocytic sorting and signaling in endothelial and other cell model systems.

Our laboratory also studies PAR function in cancer progression. PARs are overexpressed in several types of malignant cancer, transmit signals in response to tumor-generated proteases and promote tumor growth, invasion and metastasis. We have shown that inappropriate regulation of PAR signaling in invasive breast carcinoma due to dysregulated trafficking causes persistent signaling and promotes cellular invasion. PAR1 expression is also critical for breast tumor growth in vivo as assessed by mammary fat pad xenografts. We recently discovered that PAR cross-talk with ErbB family members mediates breast carcinoma invasion and metastasis. We also study the function of PAR signaling in regulation of endothelial barrier permeability and the control of breast carcinoma transendothelial cell migration.

We employ multiple approaches in our research including cutting-edge biochemical and cell biological approaches, imaging as well as animal models and tumor xenografts to study the roles of PARs in cancer progression. We are also developing systematic approaches to identify the ubiquitination machinery and other novel molecules that regulate PAR signaling using siRNA library screens. This will enable us to identify new targets for the development of drugs that can be used in the prevention and treatment of vascular diseases and cancer progression.

Recent Publications | PubMed Listing

Arora P, Cuevas B, Russo A, Johnson GL, Trejo J. (2008) Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. Oncogene Mar 13[Epub ahead of print]

Marchese A, Paing MM, Temple BRS, and Trejo J. (2008) G protein-coupled receptor sorting to endosomes and lysosomes. (Review) Ann. Rev. Pharm. Tox. 48:601-629.

Wolfe BL, Marchese A, Trejo J. (2007) Ubiquitination differentially regulates clathrin dependent internalization of protease-activated receptor-1. J. Cell Biol. 177: 905-916.

Arora P, Ricks TK, Trejo J. (2007) Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. (Review) Commentary.  J. Cell Sci., 120: 921-928.

Wolfe BL, Trejo J. (2007) Clathrin-dependent mechanisms of G protein-coupled receptor endocytosis.  (Review) Traffic, 8: 1-9.

Paing MM, Johnston CA, Siderovski DP, Trejo J. (2006) Clathrin adaptor AP-2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol. Cell. Biol., 26(8): 3221-3242.

Morris DR, Ding Y, Ricks TK, Gullapalli A, Wolfe BL, Trejo J. (2006) Protease-activated receptor-2 is essential for factors VIIa and Xa-induced signaling, migration and invasion of breast cancer cells. Cancer Res., 66(1): 307-314.