Regulation of GPCR‐induced Hippo pathway signaling by ARRDC3 in breast carcinoma

Abstract

G protein‐coupled receptors (GPCRs) are a large and diverse family of cell surface receptors implicated in cancer progression. In particular, overexpression of the GPCR protease‐activated receptor‐1 (PAR1) is associated with poor patient prognosis and metastasis of breast carcinoma. However, there remains a critical gap in knowledge of how PAR1 expression leads to breast cancer progression. Recently, the alpha‐arrestin, arrestin domain‐containing protein 3 (ARRDC3), was identified as a tumor suppressor in invasive breast carcinoma. In non‐invasive cells, ARRDC3 is essential for PAR1 trafficking and lysosomal degradation. However, ARRDC3 expression is lost in invasive breast carcinoma, resulting in dysregulated PAR1 trafficking and persistent signaling that promotes invasive breast cancer progression. Re‐expression of ARRDC3 in invasive breast carcinoma is sufficient to restore PAR1 lysosomal degradation and normal signaling, and thereby suppresses breast cancer invasion and metastasis. Moreover, ARRDC3 regulates PAR1‐stimulated Hippo pathway signaling independent of its function in regulating receptor trafficking. The Hippo pathway is driven by the activity of two transcriptional co‐activators: yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ), and is linked to cancer progression. ARRDC3 regulates GPCR‐induced Hippo pathway signaling by binding and sequestering TAZ in the cytoplasm, thus preventing nuclear translocation and transcription of genes associated with tumor metastasis and progression. Thus, ARRDC3 exhibits multiple tumor suppressor activities to control GPCR signaling in breast cancer. However, it remains unclear how GPCR activation regulates ARRDC3 function to control Hippo pathway signaling in invasive breast cancer. Here, I will present studies that interrogate various mechanisms by which GPCRs regulate Hippo pathway signaling. The results of these studies will define fundamental mechanisms by which GPCRs promote breast cancer progression via Hippo pathway signaling and vital regulatory mechanisms of the Hippo pathway that may lead to the development of new and effective therapies.