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.
Highlights
IntroductionResults: endoplasmic reticulum (ER) calcium disturbance-induced p190MetNC expression inhibits ER stress-mediated apoptosis
Both endoplasmic reticulum (ER) stress and c-Met are implicated in the tumorigenesis of hepatocellular carcinoma (HCC)
Blocking the activity of c-Met had no significant effect on the splicing of XBP-1 mRNA. These results suggest that the unfolded protein response (UPR)-specific pathways mediated by protein kinase RNA-like ER kinase (PERK)/eIF2␣, activating transcription factor 6 (ATF6), and X-box-binding protein 1 (XBP1) are not involved in the cytoprotective role of p190MetNC upon ER stress
Summary
Results: ER calcium disturbance-induced p190MetNC expression inhibits ER stress-mediated apoptosis. Conclusion: p190MetNC, but not p190Met␣, plays a critical role in promoting HCC cells survival under ER stress. P190MetNC compensates for the degradation of p190Met␣ and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. P190MetNC 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 p190MetNC. The expression of p190MetNC 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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