Integrin alpha5-induced EGFR activation by prothrombin triggers hepatocyte apoptosis via the JNK signaling pathway.
We have previously shown that prothrombin, a blood coagulation factor, can cause an inhibition of DNA synthesis in normal rat hepatocytes. To explore the mechanisms of this prothrombin action, we examined its effects on the activation of fibronectin receptor integrin alpha5, since fibronectin was found to be degraded by prothrombin actions in primary hepatocyte cultures. We found that prothrombin treatment of rat hepatocytes without addition of any growth factor induced tyrosine phosphorylation of integrin alpha5 and interaction of integrin alpha5 with epidermal growth factor receptor (EGFR), leading to EGFR tyrosine phosphorylation at tyrosine residues Tyr-845 and Tyr-1173. EGFR tyrosine phosphorylation triggered phosphorylation of its down-stream target Shc and the activation of the c-Jun N-terminal kinase (JNK) pathway. Prothrombin also induced hepatocyte apoptosis, a change in cell shape and activation of caspase 3 pathway. The JNK pathway is most likely involved in prothrombin-induced hepatocyte apoptosis, because pre-treatment of hepatocytes with JNK kinase inhibitor II (SP600125) antagonized these prothrombin actions. The data suggest that integrin-related EGFR activation by prothrombin can induce cell growth inhibition and apoptosis via an EGFR-JNK signaling pathway.
Wang
Ziqiu
Z
Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. ziqiu.wang@jefferson.edu
Wang
Meifang
M
Carr
Brian I
BI
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011516:Prothrombin / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism
D004791:Enzyme Inhibitors; D039482:Integrin alpha5; D004815:Epidermal Growth Factor; D011516:Prothrombin; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D013917:Thrombin