cosunter【300436】
Shirish Paranjpe ,William C Bowen ,Wendy M Mars ,Anne Orr ,Meagan M Haynes ,Marie C DeFrances
Receptor tyrosine kinases MET and EGFR are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also participate in the early part of the process. Regeneration employs effective redundancy schemes to compensate for the missing signals. Elimination of any single extracellular signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling (METKO+EGFRi mice) abolishes liver regeneration, prevents restoration of liver mass and leads to liver decompensation. METKO or simply EGFRi mice had distinct and signaling-specific alterations in Ser/Thr phosphorylation of mTOR, AKT, ERK1/2, PTEN, AMPKα etc. In the combined MET and EGFR signaling elimination of METKO+EGFRi mice, however, alterations dependent on either MET or EGFR combined to create shutdown of many programs vital to hepatocytes. These included decrease in expression of enzymes related to fatty acid metabolism, urea cycle, cell replication, and mitochondrial functions and increase in expression of glycolysis enzymes. There was however increase in expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control with proportional decrease in dimensions of the hepatic lobules. Mice died at 15-18 days after hepatectomy with ascites, increased plasma ammonia and very small livers.
CONCLUSION
The study shows that MET and EGFR separately control many non-overlapping signaling endpoints, allowing for compensation when only one of the signals is blocked. The combined elimination of the signals however is not tolerated. The results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. This article is protected by copyright. All rights reserved.