Role of β-Arrestin 1 in the Metastatic Progression of Colorectal Cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 5; pp. 1492 - 1497
• Main Authors: Buchanan, F. Gregory, Gorden, D. Lee, Matta, Pranathi, Shi, Qiong, Matrisian, Lynn M., DuBois, Raymond N.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31.01.2006; National Acad Sciences
• Subjects: Antibodies; Arrestins - metabolism; Arrestins - physiology; beta-Arrestin 1; beta-Arrestins; Biological Sciences; Blotting, Western; Cell adhesion & migration; Cell Line, Tumor; Cell Membrane - metabolism; Cell Movement; Collagen - chemistry; Colorectal cancer; Colorectal neoplasms; Colorectal Neoplasms - pathology; Cytosol; Cytosol - metabolism; Densitometry; Dinoprostone - metabolism; Disease Progression; Drug Combinations; Humans; Immunohistochemistry; Immunoprecipitation; Laminin - chemistry; Liver; Medical research; Metastasis; Microscopy, Fluorescence; Models, Biological; Neoplasm Metastasis; Phosphorylation; Phosphotyrosine - chemistry; Prostaglandins; Protein-Tyrosine Kinases - metabolism; Proteins; Proteoglycans - chemistry; Receptor, Epidermal Growth Factor - metabolism; Receptors; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; src-Family Kinases; Time Factors; Transactivation; Transcriptional Activation; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510562103

G protein-coupled receptor ligand-dependent transactivation of growth factor receptors has been implicated in human cancer cell proliferation, migration, and cell survival. For example, prostaglandin E₂ (PGE₂)-induced transactivation of the EGF receptor (EGFR) in colorectal carcinoma cells is mediated by means of a c-Src-dependent mechanism and regulates cell proliferation and migration. Recent evidence indicates that β-arrestin 1 may act as an important mediator in G protein-coupled receptor-induced activation of c-Src. Whether β-arrestin 1 serves a functional role in these events is, however, unknown. We investigated the effects of PGE₂ on colorectal cancer cells expressing WT and mutant β-arrestin 1. Here we report that PGE₂ induces the association of a prostaglandin E receptor 4/β-arrestin 1/c-Src signaling complex resulting in the transactivation of the EGFR and downstream Akt (PKB) signaling. The interaction of β-arrestin 1 and c-Src is critical for the regulation of colorectal carcinoma cell migration in vitro as well as metastatic spread of disease to the liver in vivo. These results show that the prostaglandin E/β-arrestin 1/c-Src signaling complex is a crucial step in PGE₂-mediated transactivation of the EGFR and may play a pivotal role in tumor metastasis. Furthermore, our data implicate a functional role for ₂-arrestin 1 as a mediator of cellular migration and metastasis.