a switch role of src in the biphasic egf signaling of er-negative breast cancer cells一个开关作用的src两相的egf er阴性乳腺癌细胞的信号.pdfVIP

A Switch Role of Src in the Biphasic EGF Signaling of ER- Negative Breast Cancer Cells ¤ XinTian Zhang, Jun Meng , Zhao-Yi Wang* Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America Abstract It is well established that epidermal growth factor (EGF) is a potent mitogen in cells expressing EGF receptor (EGFR). However, a body of evidence indicated that the effects of mitogenic EGF signaling exhibit a non-monotonic, or biphasic dose response curve; EGF at low concentrations elicits a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations, EGF inhibits cell growth. However, the molecular mechanism underlying this paradoxical effect of EGF on cell proliferation remains largely unknown. Here, we investigated the molecular mechanisms underlying the biphasic EGF signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells, both of which express endogenous EGFR. We found that EGF at low concentrations induced the phosphorylation of the Src-Y416 residue, an event to activate Src, while at high concentrations allowed Src-Y527 phosphorylation that inactivates Src. EGF at 10 ng/ml also induced phosphorylation of the MAPK/ERK and activated cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at a higher concentration (500 ng/ml). Our results thus demonstrated that Src functions as a switch of EGF signaling depending on concentrations of EGF. Citation: Zhang X, Meng J, Wang Z-Y (2012) A Switch Role of Src in the Biphasic EGF Signaling of ER-Negative Breast Cancer Cells. PLoS ONE 7(8): e41613. doi:10.1371/journal.pone.0041613 ` Editor: Antimo Migliaccio, II Universita di Napoli, Italy Received March 23, 2012; Accepted June