期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 5, 页码 1492-1497出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0510562103
关键词
metastasis; prostaglandin E-2; c-Src; EGF receptor; prostaglandin E receptor
资金
- NCI NIH HHS [P01 CA 77839, P30 CA068485, P30 CA 68485, P01 CA077839] Funding Source: Medline
- NIDDK NIH HHS [R01 DK047297, R37 DK047297, K08 DK070708, 1K08 DK 70708-01, R01 DK062112, DK 47297, DK 62112] Funding Source: Medline
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.
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