Dr. GPCR Ecosystem
Abstract
Our research goals are to delineate the regulatory mechanisms that control signaling by the G protein-coupled protease-activated receptor-1 (PAR1) and closely-related family members in normal physiology and disease.
Our recent efforts have led to the discovery that ubiquitination of a subset of GPCRs including PAR1 promotes p38 mitogen-activated protein kinase (MAPK) inflammatory signaling and not lysosomal degradation of the receptor. We also discovered a novel ubiquitin-independent lysosomal pathway for GPCRs. Contrary to conventional view, we found that ubiquitination of certain GPCRs and canonical ubiquitin-binding ESCRTs are not required for receptor lysosomal degradation. We identified ALG-interacting protein (ALIX) and the alpha-arrestin-related domain-containing protein-3 (ARRDC3) as key mediators of this GPCR lysosomal sorting pathway. The ALIX/ARRDC3-dependent pathway bypasses the requirement for GPCR ubiquitination and is distinct from the canonical ubiquitin-dependent endosomal sorting complexes required for transport (ESCRT) lysosomal pathway. Moreover, the ALIX/ARRDC3 pathway appears to be dysregulated in cancer. In recent work, we made the exciting discovery that the alpha-arrestin ARRDC3 (arrestin-domain containing protein-3), a tumor suppressor protein binds to and regulates ALIX activity, and is required for PAR1 lysosomal degradation breast carcinoma. ARRDC3 expression is either lost or suppressed in invasive triple-negative breast cancer (TNBC), a subtype of breast cancer that displays aberrant PAR1 trafficking and persistent signaling and currently lacks effective therapies. We also found that re-expression of ARRDC3 is sufficient to restore normal thrombin-activated PAR1 trafficking and signaling and suppresses breast cancer invasion. We also discovered that ARRDC3 is a multifunctional adaptor protein with dual functions that regulates GPCR Hippo signaling independent of receptor trafficking and drives TNBC metastasis in vivo.
This body of work has established new paradigms for regulation of GPCR signaling and trafficking and advanced the status of the alpha-arrestin ARRDC3 as an emerging multifaceted tumor suppressor protein with links to GPCR signal regulation in metastatic breast cancer.
About Dr. JoAnn Trejo
Dr. JoAnn Trejo earned her Ph.D. at UC San Diego. She completed her postdoctoral fellowship at UC San Francisco under the guidance of Professor Shaun Coughlin where she worked on the newly discovered protease-activated GPCRs. Dr. Trejo joined the faculty in the Department of Pharmacology at the University of North Carolina in 2000 and then moved to UC San Diego School Medicine, Department of Pharmacology in 2008, where she quickly rose through the ranks to tenured professor in 2012. In 2014, she was appointed Vice-Chair of the Department of Pharmacology.
The long-term goal of Dr. Trejo’s research program is to gain a thorough and mechanistic understanding of processes that control cell signaling by protease-activated receptors (PARs) and the impact on vascular inflammation and cancer progression. PARs are GPCRs that are activated through an atypical irreversible proteolytic mechanism. The precise control of PAR signaling is critical for proper temporal and spatial dynamics of signaling and appropriate cellular responses. Discovering new aspects of PAR signaling is important for increasing the fundamental knowledge of GPCR biology and for the identification of drug targets and future drug development. Dr. Trejo’s recent research has focused on the role of the tumor suppressor ARRDC3 on PAR1 function in breast cancer progression. She has made numerous important discoveries related to the mechanisms that control PAR1 signaling and closely-related family members and published extensively on this topic. Dr. Trejo has been continuously funded by the NIH for >20 years and was a recipient of the prestigious American Heart Association Established Investigator Award. Her laboratory is the recognized expert on protease-activated receptors, particularly PAR1, and over the years she has discovered novel aspects of GPCR biology, acquired critical expertise, and rigorous approaches to examine PAR1 function using human cultured cells and mouse models. Dr. Trejo has presented her studies at 52 national / international meetings and 66 academic seminars across the U.S.
Dr. JoAnn Trejo on the web
