Role of beta-arrestin 1 in the metastatic progression of colorectal cancer.

Buchanan FG, Gorden DL, Matta P, Shi Q, Matrisian LM, DuBois RN
Proc Natl Acad Sci U S A. 2006 103 (5): 1492-7

PMID: 16432186 · PMCID: PMC1360588 · 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 E(2) (PGE(2))-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 beta-arrestin 1 may act as an important mediator in G protein-coupled receptor-induced activation of c-Src. Whether beta-arrestin 1 serves a functional role in these events is, however, unknown. We investigated the effects of PGE(2) on colorectal cancer cells expressing WT and mutant beta-arrestin 1. Here we report that PGE(2) induces the association of a prostaglandin E receptor 4/beta-arrestin 1/c-Src signaling complex resulting in the transactivation of the EGFR and downstream Akt (PKB) signaling. The interaction of beta-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/beta-arrestin 1/c-Src signaling complex is a crucial step in PGE(2)-mediated transactivation of the EGFR and may play a pivotal role in tumor metastasis. Furthermore, our data implicate a functional role for beta-arrestin 1 as a mediator of cellular migration and metastasis.

MeSH Terms (32)

Arrestins beta-Arrestin 1 beta-Arrestins Blotting, Western Cell Line, Tumor Cell Membrane Cell Movement Collagen Colorectal Neoplasms CSK Tyrosine-Protein Kinase Cytosol Densitometry Dinoprostone Disease Progression Drug Combinations ErbB Receptors Humans Immunohistochemistry Immunoprecipitation Laminin Microscopy, Fluorescence Models, Biological Neoplasm Metastasis Phosphotyrosine Protein-Tyrosine Kinases Proteoglycans Receptors, Prostaglandin E Receptors, Prostaglandin E, EP4 Subtype Signal Transduction src-Family Kinases Time Factors Transcriptional Activation

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