Combined Systemic Disruption of MET and Epidermal Growth Factor Receptor Signaling Causes Liver Failure in Normal Mice

The American Journal of Pathology
Anastasia TsagianniGeorge K Michalopoulos

Abstract

MET and epidermal growth factor receptor (EGFR) tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently, we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration after hepatectomy, with subsequent hepatic failure and death at 15 to 18 days after resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to decreased hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions, such as fatty acid synthesis, urea cycle, and mitochondrial functions. Herein, we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling were noticeably sick by 10 days and died at 12 to 14 days. Mice with combined disruption of MET and EGFR signaling mice showed decreased liver/body weight ratios, increased apoptosis in nonparenchymal cells, impaired liver metabolic functions, and activation of distinct downstream signaling pathways related to inflammation, cell death, and survival. The present study demonstrates that, in addition to controlling the regenerativ...Continue Reading

References

Sep 1, 1988·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·P Skov OlsenE Nexø
Feb 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·Y YamadaN Fausto
Apr 4, 1997·Science·G K Michalopoulos, M C DeFrances
Mar 23, 2000·Journal of Hepatology·N Fausto
Nov 7, 2001·The American Journal of Pathology·G K MichalopoulosD B Stolz
Nov 21, 2001·Nature Cell Biology·K F Ferri, G Kroemer
Nov 28, 2002·Gastroenterology·Robert S CarverWilliam E Russell
Dec 12, 2002·The Journal of Biological Chemistry·Helena L PalkaNicholas K Tonks
Apr 9, 2004·Proceedings of the National Academy of Sciences of the United States of America·Chang-Goo HuhSnorri S Thorgeirsson
Sep 20, 2005·The Journal of Pharmacology and Experimental Therapeutics·Oksana Kaidanovich-Beilin, Hagit Eldar-Finkelman
Apr 8, 2006·Physiological Reviews·Béatrice DesvergneWalter Wahli
Jun 15, 2007·Journal of Cellular Physiology·George K Michalopoulos
Oct 18, 2007·Proceedings of the National Academy of Sciences of the United States of America·Anuradha NatarajanMaria Sibilia
Sep 30, 2008·The Journal of Biological Chemistry·Veena SangwanMorag Park
Apr 16, 2009·British Journal of Pharmacology·Geetha Vani RayasamAbhijit Ray
Apr 17, 2010·The American Journal of Pathology·Shirish ParanjpeGeorge K Michalopoulos
Nov 26, 2010·Nature Reviews. Molecular Cell Biology·Livio TrusolinoPaolo M Comoglio
Dec 1, 2011·Therapeutic Advances in Medical Oncology·Shawna Leslie Organ, Ming-Sound Tsao
Dec 6, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Laura P StabileJennifer R Grandis
Oct 22, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Shirish ParanjpeGeorge K Michalopoulos
Feb 23, 2017·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Mingjun YangLiming Tao

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Citations

Dec 7, 2018·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ian HuckUdayan Apte
Dec 12, 2018·Nature Reviews. Gastroenterology & Hepatology·Satdarshan P Monga
Jun 4, 2020·Hepatology Communications·Rodrigo M FlorentinoAlejandro Soto-Gutierrez
Aug 9, 2020·Nature Reviews. Gastroenterology & Hepatology·George K Michalopoulos, Bharat Bhushan
Apr 15, 2020·The American Journal of Pathology·Yuhua XueGeorge K Michalopoulos
Jan 18, 2019·The American Journal of Pathology·Bharat Bhushan, Udayan Apte
May 16, 2021·Seminars in Liver Disease·Nils HaepAlejandro Soto-Gutierrez
Jun 4, 2021·Nature Reviews. Molecular Cell Biology·Lara CampanaStuart Forbes
Jun 3, 2021·Scientific Reports·Olga ZbodakovaRadislav Sedlacek

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