CoChat
Sign Up
Cited by 115Liver physiology and pathologyOrgan Transplantation Techniques and OutcomesTissue Engineering and Regenerative Medicine

Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation

Open access
Paranjpe, Shirish, Bowen, William C., Mars, Wendy M., Orr, Anne, Haynes, Meagan M., DeFrances, Marie C., Liu, Silvia, Tseng, George C. +2 more·2016·Hepatology
DOI 10.1002/hep.28721PMC PMC5074871
Open this paper in CoChat — free account

Abstract

Receptor tyrosine kinases MET and epidermal growth factor receptor (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 (MET knockout + EGFR‐inhibited mice) abolishes liver regeneration, prevents restoration of liver mass, and leads to liver decompensation. MET knockout or simply EGFR‐inhibited mice had distinct and signaling‐specific alterations in Ser/Thr phosphorylation of mammalian target of rapamycin, AKT, extracellular signal–regulated kinases 1/2, phosphatase and tensin homolog, adenosine monophosphate–activated protein kinase α, etc. In the combined MET and EGFR signaling elimination of MET knockout + EGFR‐inhibited 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, increased expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control, with a proportional decrease in the dimensions of the hepatic lobules. Mice died at 15‐18 days after hepatectomy with ascites, increased plasma ammonia, and very small livers. Conclusion: MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals 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. (H epatology 2016;64:1711‐1724)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/hep.28721

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MET or EGFR signalling alone can compensate for one another, but blocking both results in deficient liver regeneration and animal death after partial hepatectomy.

    “While MET or EGFR signalling alone can compensate for one another, blocking both signalling pathways results in deficient liver regeneration, with respect to original liver mass, and animal death after partial hepatectomy.[127], [128], [129]”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [129]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. [1]Michalopoulos GK Principles of liver regeneration and growth homeostasis Compr Physiol 2013 3 485 513 23720294
  2. [2]Sakamoto T Liu Z Murase N Ezure T Yokomuro S Poli V Demetris AJ Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy Hepatology 1999 29 403 411 9918916
  3. [3]Huang W KM JZ MQ JC JL BD Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration Science 2006 312 233 236 16614213
  4. [4]Yamada Y Webber EM Kirillova I Peschon JJ Fausto N Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor [comment] Hepatology 1998 28 959 970 9755232
  5. [5]Tan X Behari J Cieply B Michalopoulos GK Monga SP Conditional deletion of beta-catenin reveals its role in liver growth and regeneration Gastroenterology 2006 131 1561 1572 17101329
  6. [6]Ochoa B Syn WK Delgado I Karaca GF Jung Y Wang J Zubiaga AM Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice Hepatology 2010 51 1712 1723 20432255 PMC2920129
  7. [7]Kong B Huang J Zhu Y Li G Williams J Shen S Aleksunes LM Fibroblast growth factor 15 deficiency impairs liver regeneration in mice Am J Physiol Gastrointest Liver Physiol 2014 306 G893 902 24699334 PMC4024724
  8. [9]Paranjpe S Bowen WC Tseng GC Luo JH Orr A Michalopoulos GK RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in rats Am J Pathol 2010 176 2669 2681 20395437 PMC2877830
  9. [10]Nejak-Bowen K Orr A Bowen WC Jr Michalopoulos GK Conditional genetic elimination of hepatocyte growth factor in mice compromises liver regeneration after partial hepatectomy PLoS One 2013 8 e59836 23527275 PMC3603894
  10. [11]Natarajan A Wagner B Sibilia M The EGF receptor is required for efficient liver regeneration Proc Natl Acad Sci U S A 2007 104 17081 17086 17940036 PMC2040457
  11. [12]Carver RS Stevenson MC Scheving LA Russell WE Diverse expression of ErbB receptor proteins during rat liver development and regeneration Gastroenterology 2002 123 2017 2027 12454858
  12. [13]Borowiak M Garratt AN Wustefeld T Strehle M Trautwein C Birchmeier C Met provides essential signals for liver regeneration Proc Natl Acad Sci U S A 2004 101 10608 10613 15249655 PMC490025
  13. [14]Huh CG Factor VM Sanchez A Uchida K Conner EA Thorgeirsson SS Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair Proc Natl Acad Sci U S A 2004 101 4477 4482 15070743 PMC384772
  14. [15]Scheving LA Zhang X Stevenson MC Threadgill DW Russell WE Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice Am J Physiol Gastrointest Liver Physiol 2015 308 G364 377 25414100 PMC4346751
  15. [16]Lopez-Luque J Caballero-Diaz D Martinez-Palacian A Roncero C Moreno-Caceres J Garcia-Bravo M Grueso E Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis Hepatology 2016 63 604 619 26313466
  16. [17]Smaill JB Rewcastle GW Loo JA Greis KD Chan OH Reyner EL Lipka E Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions J Med Chem 2000 43 1380 1397 10753475
  17. [18]Slichenmyer WJ Elliott WL Fry DW CI-1033, a pan-erbB tyrosine kinase inhibitor Semin Oncol 2001 28 80 85 11706399
  18. [19]Ciardiello F Tortora G A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor Clin Cancer Res 2001 7 2958 2970 11595683
  19. [20]Longati P Bardelli A Ponzetto C Naldini L Comoglio PM Tyrosines1234–1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor) Oncogene 1994 9 49 57 8302603
  20. [21]Ponzetto C Bardelli A Zhen Z Maina F dalla Zonca P Giordano S Graziani A A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family Cell 1994 77 261 271 7513258
  21. [22]Kwon Y Smith BD Zhou Y Kaufman MD Godwin AK Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment Oncogene 2015 34 144 153 24362531 PMC4067476
  22. [23]Gomes DA Rodrigues MA Leite MF Gomez MV Varnai P Balla T Bennett AM c-Met must translocate to the nucleus to initiate calcium signals J Biol Chem 2008 283 4344 4351 18073207 PMC2825875
  23. [24]Belaus A Merkle C Fritsche M Groner B Crosstalk between the extracellular domain of the ErbB2 receptor and IGF-1 receptor signaling J Steroid Biochem Mol Biol 2003 85 105 115 12943694
  24. [25]Lu WY Bird TG Boulter L Tsuchiya A Cole AM Hay T Guest RV Hepatic progenitor cells of biliary origin with liver repopulation capacity Nat Cell Biol 2015 PMC4612439 26192438
  25. [26]Trautwein C Will M Kubicka S Rakemann T Flemming P Manns MP 2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression Oncogene 1999 18 6443 6453 10597246
  26. [27]Fouraschen SM de Ruiter PE Kwekkeboom J de Bruin RW Kazemier G Metselaar HJ Tilanus HW mTOR signaling in liver regeneration: Rapamycin combined with growth factor treatment World J Transplant 2013 3 36 47 24255881 PMC3832859
  27. [28]Copp J Manning G Hunter T TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2 Cancer Res 2009 69 1821 1827 19244117 PMC2652681
  28. [29]Pauta M Rotllan N Fernandez-Hernando A Langhi C Ribera J Lu M Boix L Akt-mediated foxo1 inhibition is required for liver regeneration Hepatology 2016 63 1660 1674 26473496 PMC5177729
  29. [30]Sarbassov DD Guertin DA Ali SM Sabatini DM Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Science 2005 307 1098 1101 15718470
  30. [31]Vazquez F Ramaswamy S Nakamura N Sellers WR Phosphorylation of the PTEN tail regulates protein stability and function Mol Cell Biol 2000 20 5010 5018 10866658 PMC85951
  31. [33]Motoshima H Goldstein BJ Igata M Araki E AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer J Physiol 2006 574 63 71 16613876 PMC1817805
  32. [34]Shackelford DB Shaw RJ The LKB1-AMPK pathway: metabolism and growth control in tumour suppression Nat Rev Cancer 2009 9 563 575 19629071 PMC2756045
  33. [35]Ha J Daniel S Broyles SS Kim KH Critical phosphorylation sites for acetyl-CoA carboxylase activity J Biol Chem 1994 269 22162 22168 7915280
  34. [36]Tseng GC Wong HW Tight Clustering: A resampling-based approach for identifying stable and tight patterns in data Biometrics 2005 61 10 16 15737073
  35. [37]Gomez-Quiroz LE Factor VM Kaposi-Novak P Coulouarn C Conner EA Thorgeirsson SS Hepatocyte-specific c-Met deletion disrupts redox homeostasis and sensitizes to Fas-mediated apoptosis J Biol Chem 2008 283 14581 14589 18348981 PMC2386934
  36. [38]Tian J Locker J Gadd45 in the liver: signal transduction and transcriptional mechanisms Adv Exp Med Biol 2013 793 69 80 24104474
  37. [39]Masumoto A Yamamoto N Sequestration of a hepatocyte growth factor in extracellular matrix in normal adult rat liver Biochem Biophys Res Commun 1991 174 90 95 1824922
  38. [40]Olsen PS Poulsen SS Kirkegaard P Adrenergic effects on secretion of epidermal growth factor from Brunner’s glands Gut 1985 26 920 927 2863199 PMC1432851
  39. [41]Ichikawa T Zhang YQ Kogure K Hasegawa Y Takagi H Mori M Kojima I Transforming growth factor beta and activin tonically inhibit DNA synthesis in the rat liver Hepatology 2001 34 918 925 11679962
  40. [42]Webber EM Bruix J Pierce RH Fausto N Tumor necrosis factor primes hepatocytes for DNA replication in the rat Hepatology 1998 28 1226 1234 9794905
  41. [44]Pediaditakis P Lopez-Talavera JC Petersen B Monga SP Michalopoulos GK The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat Hepatology 2001 34 688 693 11584364 PMC1821089
  42. [45]Mars WM Liu ML Kitson RP Goldfarb RH Gabauer MK Michalopoulos GK Immediate early detection of urokinase receptor after partial hepatectomy and its implications for initiation of liver regeneration Hepatology 1995 21 1695 1701 7768515
  43. [46]Shiota G Okano J Kawasaki H Kawamoto T Nakamura T Serum hepatocyte growth factor levels in liver diseases: clinical implications Hepatology 1995 21 106 112 7806142
  44. [47]Arakaki N Kawakami S Nakamura O Ohnishi T Miyazaki H Ishii T Tsubouchi H Evidence for the presence of an inactive precursor of human hepatocyte growth factor in plasma and sera of patients with liver diseases Hepatology 1995 22 1728 1734 7489981
  45. [48]Le Bail B Bioulac-Sage P Senuita R Quinton A Saric J Balabaud C Fine structure of hepatic sinusoids and sinusoidal cells in disease J Electron Microsc Tech 1990 14 257 282 2338589
  46. [49]Block GD Locker J Bowen WC Petersen BE Katyal S Strom SC Riley T Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium J Cell Biol 1996 132 1133 1149 8601590 PMC2120765
  47. [50]Limaye PB Bowen WC Orr AV Luo J Tseng GC Michalopoulos GK Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium Hepatology 2008 47 1702 1713 18398918 PMC2615562

Cited by

Sorted by citations

Authors
Paranjpe, S., Bowen, W. C., Mars, W. M., Orr, A., Haynes, M. M., DeFrances, M. C., Liu, S., Tseng, G. C., Tsagianni, A., & Michalopoulos, G. K.
Affiliations
University of Pittsburgh (US)
Corresponding author
Michalopoulos, George K.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-10-01
Volume
64
Issue
5
Pages
1711-1724
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.28721
PMC
PMC5074871
OpenAlex
W2528937381
Cited by
115
References
3
Citations by year
2026: 6 · 2025: 11 · 2024: 18 · 2023: 12 · 2022: 10 · 2021: 12 · 2020: 17 · 2019: 6 · 2018: 9 · 2017: 12 · 2016: 2
FWCI
6.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cleveland Foundation
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK096990)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
MET receptor tyrosine kinase, epidermal growth factor receptor, liver regeneration, hepatic decompensation, hepatectomy, EGFR inhibition, MAPK signaling, PI3K/Akt signaling, AMPK, phosphatase and tensin homolog, fatty acid metabolism, urea cycle, glycolysis, plasma proteins, hepatocyte volume, blood ammonia
MeSH terms
Animals, Liver Regeneration, Male, Signal Transduction, Liver Failure, Proto-Oncogene Proteins c-met, Mice, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review