Role of beta-arrestin 1 in the metastatic progression of colorectal cancer.
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.
Buchanan
F Gregory
FG
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 661 PRB, 2220 Pierce Avenue, Nashville, TN 37232, USA.
Gorden
D Lee
DL
Matta
Pranathi
P
Shi
Qiong
Q
Matrisian
Lynn M
LM
DuBois
Raymond N
RN
D019390:Arrestins / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D015179:Colorectal Neoplasms / Q000473:pathology*; D003600:Cytosol / Q000378:metabolism; D003720:Densitometry; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007797:Laminin / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009362:Neoplasm Metastasis; D019000:Phosphotyrosine / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019061:src-Family Kinases
C000605253:ARRB1 protein, human; D019390:Arrestins; D004338:Drug Combinations; D007797:Laminin; C545650:PTGER4 protein, human; D011509:Proteoglycans; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C059485:matrigel; D019000:Phosphotyrosine; D003094:Collagen; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D015232:Dinoprostone