Graduate Student University of California, San Diego
Helen Wedegaertner (University of California, San Diego)| JoAnn Trejo (University of California, San Diego)
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are known to play key roles in human health and disease, such as cancer. However, while they have proven to be highly druggable, GPCRs are widely underutilized as drug targets in cancer. In cancer, although GPCR signaling is known to be altered, GPCRs themselves are rarely mutated, and therefore it is important that we better understand how GPCR signaling is regulated. Protease-activated receptor-1 (PAR1), the GPCR for thrombin, has been shown to be a key driver of invasive breast cancer progression. We recently demonstrated that PAR1 is regulated by arrestin domain-containing protein-3 (ARRDC3), a member of the newly discovered family of α-arrestins. Humans express both β- and α-arrestins, and while these families share very little sequence homology, they are predicted to be structurally similar, and therefore may be subject to similar regulatory mechanisms. However, while GPCR regulation of β-arrestin function has been well characterized, it remains entirely unknown how GPCRs might regulate α-arrestins, such as ARRDC3. Here, by using a variety of biochemical and microscopy-based techniques, we show that PAR1 may regulate ARRDC3 through modulation of post-translational modifications, including ubiquitination, and that identified ARRDC3 regulatory domains may play a role in its subcellular localization. We hypothesize that PAR1-mediated regulation of ARRDC3 is critical for normal ARRDC3 function. We will use a variety of approaches to elucidate the role of ARRDC3 regulatory mechanisms in its function in regulating PAR1 signaling and trafficking and breast cancer progression. The results of these studies will advance our understanding of how PAR1 signaling is regulated and may lead to identification of novel targets for therapeutic development to treat breast cancer.
Support or Funding Information
Tobacco-Related Disease Research Program Pre-Doctoral Award, T31DT1550
UCSD Graduate Training Program in Cellular and Molecular Pharmacology through NIH General Medical Sciences, T32 GM007752