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PMID: 11381087 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice.

The Journal of cell biology ·Vol. 153 ·No. 5 ·2001-05-28 ·Pages 1023-34

Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM

Abstract

Overexpression is the most common abnormality of receptor tyrosine kinases (RTKs) in human tumors. It is presumed that overexpression leads to constitutive activation of RTKs, but the mechanism of that activation has been uncertain. Here we show that overexpression of the Met RTK allows activation of the receptor by cell attachment and that this form of activation can be tumorigenic. Transgenic mice that overexpressed Met in hepatocytes developed hepatocellular carcinoma (HCC), one of the human tumors in which Met has been implicated previously. The tumorigenic Met was activated by cell attachment rather than by ligand. Inactivation of the transgene led to regression of even highly advanced tumors, apparently mediated by apoptosis and cessation of cellular proliferation. These results reveal a previously unappreciated mechanism by which the tumorigenic action of RTKs can be mediated, provide evidence that Met may play a role in both the genesis and maintenance of HCC, and suggest that Met may be a beneficial therapeutic target in tumors that overexpress the receptor.

MeSH Terms
Animals Apoptosis Carcinoma, Hepatocellular/enzymology,genetics,pathology Cell Adhesion Cell Division Cell Survival Cells, Cultured Doxycycline/pharmacology Enzyme Activation HeLa Cells Hepatocyte Growth Factor/pharmacology Hepatocytes/drug effects,enzymology,metabolism,pathology Humans Ligands Mice Mice, Transgenic Phosphorylation Proto-Oncogene Proteins c-met/genetics,metabolism Signal Transduction Transgenes/genetics Tumor Cells, Cultured
Chemicals
Ligands Hepatocyte Growth Factor Proto-Oncogene Proteins c-met Doxycycline
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang R
G.W. Hooper Foundation and Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143, USA. rwang@cgl.ucsf.edu
Ferrell L D
Faouzi S
Maher J J
Bishop J M
References (54)
54 references, click to expand
  1. Scatter factor receptors are key players in a unique multistep program leading to invasive growth.
    Ciba Found Symp. 1997;212:133-44; discussion 144-7 PMID: 9524768
  2. Met-HGF/SF: tumorigenesis, invasion and metastasis.
    Ciba Found Symp. 1997;212:119-30; discussion 130-2, 148-54 PMID: 9524767
  3. The mutationally activated Met receptor mediates motility and metastasis.
    Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14417-22 PMID: 9826715
  4. Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas.
    Cancer Res. 1999 Jan 15;59(2):307-10 PMID: 9927037
  5. Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice.
    Nat Biotechnol. 1999 Feb;17(2):165-9 PMID: 10052353
  6. Transient excess of MYC activity can elicit genomic instability and tumorigenesis.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3940-4 PMID: 10097142
  7. Interactions between mitogenic stimuli, or, a thousand and one connections.
    Curr Opin Cell Biol. 1999 Apr;11(2):197-202 PMID: 10209147
  8. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family.
    Int J Cancer. 1999 Aug 27;82(5):640-3 PMID: 10417759
  9. Integrin signaling.
    Science. 1999 Aug 13;285(5430):1028-32 PMID: 10446041
  10. The hallmarks of cancer.
    Cell. 2000 Jan 7;100(1):57-70 PMID: 10647931
  11. Hepatocyte growth factor/scatter factor-induced intracellular signalling.
    Int J Exp Pathol. 2000 Feb;81(1):17-30 PMID: 10718861
  12. Hepatocellular carcinoma.
    J Hepatol. 2000;32(1 Suppl):225-37 PMID: 10728807
  13. Flipping the oncogene switch: illumination of tumor maintenance and regression.
    Trends Genet. 2000 Apr;16(4):147-50 PMID: 10729826
  14. Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.
    Oncogene. 2000 Mar 16;19(12):1547-55 PMID: 10734314
  15. Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src.
    J Biol Chem. 2000 May 19;275(20):14783-6 PMID: 10747844
  16. Parenchymal cells from adult rat liver in nonproliferating monolayer culture. I. Functional studies.
    J Cell Biol. 1973 Dec;59(3):722-34 PMID: 4357460
  17. Molecular cloning of a new transforming gene from a chemically transformed human cell line.
    Nature. 1984 Sep 6-11;311(5981):29-33 PMID: 6590967
  18. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors.
    Proc Natl Acad Sci U S A. 1987 Sep;84(18):6379-83 PMID: 2819873
  19. Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases.
    Proc Natl Acad Sci U S A. 1988 Jan;85(1):21-5 PMID: 3277171
  20. Biosynthesis of the protein encoded by the c-met proto-oncogene.
    Oncogene. 1989 Nov;4(11):1383-8 PMID: 2554238
  21. Marked increase of HGF mRNA in non-parenchymal liver cells of rats treated with hepatotoxins.
    Biochem Biophys Res Commun. 1989 Dec 29;165(3):1229-34 PMID: 2692563
  22. Molecular themes in oncogenesis.
    Cell. 1991 Jan 25;64(2):235-48 PMID: 1988146
  23. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product.
    Science. 1991 Feb 15;251(4995):802-4 PMID: 1846706
  24. The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation.
    Mol Cell Biol. 1991 Apr;11(4):1793-803 PMID: 2005882
  25. Structure, tissue-specific expression, and transforming activity of the mouse met protooncogene.
    Cell Growth Differ. 1990 Feb;1(2):87-95 PMID: 2085463
  26. Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET.
    Oncogene. 1991 Apr;6(4):501-4 PMID: 1827664
  27. c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase.
    Oncogene. 1991 Apr;6(4):553-9 PMID: 1674365
  28. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor.
    EMBO J. 1991 Oct;10(10):2867-78 PMID: 1655405
  29. The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors.
    Int J Cancer. 1991 Sep 30;49(3):323-8 PMID: 1917129
  30. Identification of the major autophosphorylation site of the Met/hepatocyte growth factor receptor tyrosine kinase.
    J Biol Chem. 1991 Oct 15;266(29):19558-64 PMID: 1655790
  31. Scatter factor and hepatocyte growth factor: activities, properties, and mechanism.
    Cell Growth Differ. 1992 Jan;3(1):11-20 PMID: 1534687
  32. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor.
    Mol Cell Biol. 1992 Nov;12(11):5152-8 PMID: 1406687
  33. The c-met/HGF receptor in human tumours.
    Eur J Cancer Prev. 1992 Oct;1 Suppl 3:45-9 PMID: 1467788
  34. Molecular characteristics of HGF-SF and its role in cell motility and invasion.
    EXS. 1993;65:311-28 PMID: 8380739
  35. Proposal for standardized criteria for the diagnosis of benign, borderline, and malignant hepatocellular lesions arising in chronic advanced liver disease.
    Am J Surg Pathol. 1993 Nov;17(11):1113-23 PMID: 8214256
  36. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.
    Cell. 1994 Apr 22;77(2):261-71 PMID: 7513258
  37. Hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells requires phosphatidylinositol 3-kinase.
    J Biol Chem. 1995 Nov 17;270(46):27780-7 PMID: 7499247
  38. Expression of constitutively activated hepatocyte growth factor/scatter factor receptor (c-met) in B16 melanoma cells selected for enhanced liver colonization.
    Oncogene. 1995 Nov 16;11(10):1979-87 PMID: 7478516
  39. Stimulation of beta1 integrins on fibroblasts induces PDGF independent tyrosine phosphorylation of PDGF beta-receptors.
    J Cell Biol. 1996 Feb;132(4):741-52 PMID: 8647902
  40. Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors.
    J Clin Invest. 1996 Jun 15;97(12):2872-7 PMID: 8675700
  41. Gene expressions of c-met and hepatocyte growth factor in chronic liver disease and hepatocellular carcinoma.
    J Hepatol. 1996 Mar;24(3):286-92 PMID: 8778194
  42. Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does.
    Hepatology. 1996 Jul;24(1):60-4 PMID: 8707284
  43. Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor.
    Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8425-30 PMID: 8710887
  44. Constitutive activation of c-Met in liver metastatic B16 melanoma cells depends on both substrate adhesion and cell density and is regulated by a cytosolic tyrosine phosphatase activity.
    J Biol Chem. 1996 Aug 23;271(34):20763-9 PMID: 8702829
  45. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice.
    Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10933-8 PMID: 8855286
  46. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis.
    Nature. 1996 Nov 14;384(6605):173-6 PMID: 8906793
  47. Cooperation between soluble factors and integrin-mediated cell anchorage in the control of cell growth and differentiation.
    Bioessays. 1996 Nov;18(11):911-7 PMID: 8939069
  48. Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes.
    EMBO J. 1997 Feb 3;16(3):495-503 PMID: 9034332
  49. Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma.
    Hepatology. 1997 Mar;25(3):619-23 PMID: 9049208
  50. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.
    Nat Genet. 1997 May;16(1):68-73 PMID: 9140397
  51. A point mutation in the MET oncogene abrogates metastasis without affecting transformation.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13868-72 PMID: 9391119
  52. Expression of the HGF/SF receptor, c-met, and its ligand in human colorectal cancers.
    Cancer Invest. 1997;15(6):513-21 PMID: 9412656
  53. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway.
    Nature. 1998 Jan 15;391(6664):285-8 PMID: 9440692
  54. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase.
    Trends Cell Biol. 1998 Oct;8(10):404-10 PMID: 9789329
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.153.5.1023
Email
rwang@cgl.ucsf.edu
Published
2001-05-28
Pages
1023-34
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2174327
Subset
IM
Grants
NIDDK NIH HHS · P30 DK026743 · United States
NIDDK NIH HHS · 5P30 DK26743 · United States
NCI NIH HHS · CA44338 · United States
External Links
PubMed source DOI: 10.1083/jcb.153.5.1023 PMC Full Text View journal details
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