Hepassocin activates the EGFR/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway.
Hepassocin (HPS) is a secreted protein with mitogenic activity on primary hepatocytes and protects hepatocytes from chemically-induced injury. Our previous studies showed that HPS stimulates proliferation of hepatocytes in an ERK pathway-dependent manner. However, the molecular mechanism of HPS-induced activation of the ERK pathway remains unclear. In this study, we found that HPS induced the phosphorylation of the epidermal growth factor receptor (EGFR) in the human L02 hepatocyte cell line, and this event was concomitant with the activation of the non-receptor tyrosine kinase Src. Specific inhibition of EGFR kinase activity by gefitinib or down-regulation of EGFR by specific EGFR siRNAs prevented HPS-induced activation of the ERK pathway and proliferation of L02 cells. Furthermore, inhibition of Src activity significantly blocked HPS-induced activation of the EGFR, which was suggestive of a ligand-independent transactivation mechanism of EGFR itself as well as ERK phosphorylation and proliferation of L02 cells. These results indicate that EGFR plays an important role in the mitogenic signaling induced by HPS in L02 cell lines and may further stimulate research on the role of HPS in hepatocytes within biological processes in human health and disease.
Tianjin University, Department of Pharmaceutical Engineering, Tianjin 300072, China; Beijing Institute of Radiation Medicine, Beijing 100850, China.
Ming
M
Gao
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Yi-Qun
YQ
Zhan
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Miao
M
Yu
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Chang-Hui
CH
Ge
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Chang-Yan
CY
Li
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Jian-Hong
JH
Zhang
Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China.
Xiao-Hui
XH
Wang
Tianjin University, Department of Pharmaceutical Engineering, Tianjin 300072, China.
Zhi-Qiang
ZQ
Ge
Tianjin University, Department of Pharmaceutical Engineering, Tianjin 300072, China; Beijing Institute of Radiation Medicine, Beijing 100850, China; State Key Laboratory of Proteomics, Beijing 100850, China. Electronic address: xiaomingyang@sina.com.
Xiao-Ming
XM
Yang
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005340:Fibrinogen; D000077156:Gefitinib; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C485894:FGL1 protein, human; D009363:Neoplasm Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D005340:Fibrinogen; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib
EGFR; ERK; HPS; Src; Transactivation