Matriptase Regulated EGFR Signaling Pathway To Promote Cancer Cells Invasion And Metastasis

Oncogenic proteins cooperate to promote tumor development by maintaining cell proliferation,invasion and metastasis.Matriptase is a type II transmembrane serine protease derived from epithelium.It plays an important role in maintaining normal epithelial cell biology.However,its dysregulation is highly related to the development and metastasis of tumors.Epidermal growth factor receptor(EGFR)is one of the most widely studied tyrosine kinase receptors(RTKs).Abnormal cascades of EGFR signals are also connected with cancer invasion and metastasis,leading to the development of a variety of human tumors.Preliminary studies have shown a correlation between Matriptase and EGFR in tumor development.But how exactly they are involved in the development of malignant tumors is poorly understood.Therefore,we aimed to explore the more detailed relationship between Matriptase and EGFR in tumorigenesis.This study demonstrated the crosstalk between Matriptase and EGFR.EGF promoted the activity of EGFR tyrosine kinase to activate Matriptase,which enhanced the protease activation of Matriptase.On the contrary,Matriptase acted as a key regulator of EGFR signaling.And it was critical to the intensity and duration of EGFR signaling pathway.We found a direct interaction between Matriptase and EGFR.Matriptase promoted EGF-induced EGFR phosphorylation and ubiquitination.And it also regulated EGFR endocytosis.Matriptase could significantly amplified the EGFR short-term signaling.Moreover,Induced by EGF for a long time,Matriptase was involved in the up-regulation of pro-HGF(hepatocyte growth factor)induced by the EGFR/JNK signaling axis.And EGF-activated Matriptase mediated activation of proHGF.The dual regulation of Matriptase on the expression and activation of pro-HGF triggered the activation of HGF/c-Met signaling,which generated a second wave of signaling.Finally,Matriptase and EGFR synergistically promoted invasion and metastasis of cancer cells.This study further confirmed the important role of Matriptase in inducing metastasis and invasion of cancer cells,which provided a complementary mechanism for how Matriptase promotes tumorigenesis and development.More importantly,the results indicated that Matriptase played an important role in regulating EGFR signaling.It revealed the intrinsic relationship between Matriptase,EGFR,and c-Met in promoting invasion and metastasis of cancer cells.It indicated that Matriptase can be used as a potential drug target.By inhibiting the activity of Matriptase,it can inhibit the activity of EGFR and c-Met,achieving the treatment of tumor.