title: Disturbance of Ca2+ homeostasis converts pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells.
abstract: c-Met, the tyrosine-kinase receptor for hepatocyte growth factor, plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains incompletely understood. The mature c-Met protein p190Met(αβ) (consists of a α subunit and a β subunit) is processed from pro-Met. Here we show that pro-Met is processed into p190Met(NC) by sarco/endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin. p190Met(NC) compensates for the degradation of p190Met(αβ) and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. In comparison with p190Met(αβ), p190Met(NC) is not cleaved and is expressed as a single-chain polypeptide. Thapsigargin-initiated p190Met(NC) expression depends on the disturbance of ER calcium homeostasis. Once induced, p190Met(NC) is activated independent of hepatocyte growth factor engagement. p190Met(NC) contributes to sustained high basal activation of c-Met downstream pathways during ER calcium disturbance-mediated ER stress. Both p38 MAPK-promoted glucose-regulated protein 78 (GRP78) expression and sustained high basal activation of PI3K/Akt and MEK/ERK are involved in the cytoprotective function of p190Met(NC). Importantly, the expression of p190Met(NC) is detected in some HCC cases. Taken together, these data provide a potential mechanism to explain how c-Met promotes HCC cells survival in response to ER stress. We propose that context-specific processing of c-Met protein is implicated in HCC progression in stressful microenvironments.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
authors.forename: Rongyang
authors.initials: R
authors.lastname: Dai
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Lexing
authors.initials: L
authors.lastname: Yu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhao
authors.forename: Youwen
authors.initials: Y
authors.lastname: Qian
authors.forename: Huilu
authors.initials: H
authors.lastname: Zhang
authors.forename: Haiyang
authors.initials: H
authors.lastname: Chen
authors.forename: Yibin
authors.initials: Y
authors.lastname: Ren
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics; D008297:Male; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717247:HSPA5 protein, human; D011518:Proto-Oncogene Proteins; D019284:Thapsigargin; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium