Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 18, Pages 14586-14597Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.333435
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Funding
- National Natural Science Foundation of China [81000886, 81170377, 81101714, 30921006, 91029732]
- State Key Project for Infectious Diseases [2012ZX10002-009]
- New Century Excellent Talents in University
- State Key Laboratory of Oncogenes and Related Genes [91-10-02, 90-10-03, 90-09-06, 10JC1418500]
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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(alpha beta) (consists of a alpha subunit and a beta 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. p190MetNC compensates for the degradation of p190Met(alpha beta) and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. In comparison with p190Met(alpha beta), 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.
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