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. 1995 Mar 28;92(7):2597–2601. doi: 10.1073/pnas.92.7.2597

Mutation of juxtamembrane tyrosine residue 1001 suppresses loss-of-function mutations of the met receptor in epithelial cells.

K M Weidner 1, M Sachs 1, D Riethmacher 1, W Birchmeier 1
PMCID: PMC42265  PMID: 7708691

Abstract

Signals transduced by the met tyrosine kinase, which is the receptor for scatter factor/hepatocyte growth factor, are of major importance for the regulation of epithelial cell motility, morphogenesis, and proliferation. We report here that different sets of tyrosine residues in the cytoplasmic domain of the met receptor affect signal transduction in epithelial cells in a positive or negative fashion: mutation of the C-terminal tyrosine residues 13-16 (Y1311, Y1347, Y1354, and Y1363) reduced or abolished ligand-induced cell motility and branching morphogenesis. In contrast, mutation of the juxtamembrane tyrosine residue 2 (Y1001) produced constitutively mobile, fibroblastoid cells. Furthermore, the gain-of-function mutation of tyrosine residue 2 suppressed the loss-of-function mutations of tyrosine residue 15 or 16. The opposite roles of the juxtamembrane and C-terminal tyrosine residues may explain the suggested dual function of the met receptor in both epithelial-mesenchymal interactions and tumor progression.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bièche I., Champème M. H., Matifas F., Hacène K., Callahan R., Lidereau R. Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet. 1992 Jan 18;339(8786):139–143. doi: 10.1016/0140-6736(92)90208-k. [DOI] [PubMed] [Google Scholar]
  2. Bottaro D. P., Rubin J. S., Faletto D. L., Chan A. M., Kmiecik T. E., Vande Woude G. F., Aaronson S. A. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991 Feb 15;251(4995):802–804. doi: 10.1126/science.1846706. [DOI] [PubMed] [Google Scholar]
  3. Deng W. P., Nickoloff J. A. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site. Anal Biochem. 1992 Jan;200(1):81–88. doi: 10.1016/0003-2697(92)90280-k. [DOI] [PubMed] [Google Scholar]
  4. Egan S. E., Weinberg R. A. The pathway to signal achievement. Nature. 1993 Oct 28;365(6449):781–783. doi: 10.1038/365781a0. [DOI] [PubMed] [Google Scholar]
  5. Feng G. S., Hui C. C., Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993 Mar 12;259(5101):1607–1611. doi: 10.1126/science.8096088. [DOI] [PubMed] [Google Scholar]
  6. Gherardi E., Stoker M. Hepatocyte growth factor--scatter factor: mitogen, motogen, and met. Cancer Cells. 1991 Jun;3(6):227–232. [PubMed] [Google Scholar]
  7. Gonzatti-Haces M., Seth A., Park M., Copeland T., Oroszlan S., Vande Woude G. F. 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):21–25. doi: 10.1073/pnas.85.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grant D. S., Kleinman H. K., Goldberg I. D., Bhargava M. M., Nickoloff B. J., Kinsella J. L., Polverini P., Rosen E. M. Scatter factor induces blood vessel formation in vivo. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1937–1941. doi: 10.1073/pnas.90.5.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Graziani A., Gramaglia D., dalla Zonca P., Comoglio P. M. Hepatocyte growth factor/scatter factor stimulates the Ras-guanine nucleotide exchanger. J Biol Chem. 1993 May 5;268(13):9165–9168. [PubMed] [Google Scholar]
  10. Hartmann G., Weidner K. M., Schwarz H., Birchmeier W. The motility signal of scatter factor/hepatocyte growth factor mediated through the receptor tyrosine kinase met requires intracellular action of Ras. J Biol Chem. 1994 Sep 2;269(35):21936–21939. [PubMed] [Google Scholar]
  11. Huff J. L., Jelinek M. A., Borgman C. A., Lansing T. J., Parsons J. T. The protooncogene c-sea encodes a transmembrane protein-tyrosine kinase related to the Met/hepatocyte growth factor/scatter factor receptor. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6140–6144. doi: 10.1073/pnas.90.13.6140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Longati P., Bardelli A., Ponzetto C., Naldini L., Comoglio P. M. Tyrosines1234-1235 are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor). Oncogene. 1994 Jan;9(1):49–57. [PubMed] [Google Scholar]
  13. Miyazawa K., Tsubouchi H., Naka D., Takahashi K., Okigaki M., Arakaki N., Nakayama H., Hirono S., Sakiyama O., Takahashi K. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun. 1989 Sep 15;163(2):967–973. doi: 10.1016/0006-291x(89)92316-4. [DOI] [PubMed] [Google Scholar]
  14. Montesano R., Matsumoto K., Nakamura T., Orci L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell. 1991 Nov 29;67(5):901–908. doi: 10.1016/0092-8674(91)90363-4. [DOI] [PubMed] [Google Scholar]
  15. Nakamura T., Nishizawa T., Hagiya M., Seki T., Shimonishi M., Sugimura A., Tashiro K., Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440–443. doi: 10.1038/342440a0. [DOI] [PubMed] [Google Scholar]
  16. Naldini L., Weidner K. M., Vigna E., Gaudino G., Bardelli A., Ponzetto C., Narsimhan R. P., Hartmann G., Zarnegar R., Michalopoulos G. K. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991 Oct;10(10):2867–2878. doi: 10.1002/j.1460-2075.1991.tb07836.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nishimura R., Li W., Kashishian A., Mondino A., Zhou M., Cooper J., Schlessinger J. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. Mol Cell Biol. 1993 Nov;13(11):6889–6896. doi: 10.1128/mcb.13.11.6889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ponzetto C., Bardelli A., Maina F., Longati P., Panayotou G., Dhand R., Waterfield M. D., Comoglio P. M. A novel recognition motif for phosphatidylinositol 3-kinase binding mediates its association with the hepatocyte growth factor/scatter factor receptor. Mol Cell Biol. 1993 Aug;13(8):4600–4608. doi: 10.1128/mcb.13.8.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ponzetto C., Bardelli A., Zhen Z., Maina F., dalla Zonca P., Giordano S., Graziani A., Panayotou G., Comoglio P. M. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994 Apr 22;77(2):261–271. doi: 10.1016/0092-8674(94)90318-2. [DOI] [PubMed] [Google Scholar]
  20. Ronsin C., Muscatelli F., Mattei M. G., Breathnach R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene. 1993 May;8(5):1195–1202. [PubMed] [Google Scholar]
  21. Shiota G., Rhoads D. B., Wang T. C., Nakamura T., Schmidt E. V. Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):373–377. doi: 10.1073/pnas.89.1.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Soman N. R., Correa P., Ruiz B. A., Wogan G. N. The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4892–4896. doi: 10.1073/pnas.88.11.4892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sonnenberg E., Meyer D., Weidner K. M., Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993 Oct;123(1):223–235. doi: 10.1083/jcb.123.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stoker M., Gherardi E., Perryman M., Gray J. Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature. 1987 May 21;327(6119):239–242. doi: 10.1038/327239a0. [DOI] [PubMed] [Google Scholar]
  25. Tsarfaty I., Resau J. H., Rulong S., Keydar I., Faletto D. L., Vande Woude G. F. The met proto-oncogene receptor and lumen formation. Science. 1992 Aug 28;257(5074):1258–1261. doi: 10.1126/science.1387731. [DOI] [PubMed] [Google Scholar]
  26. Tsarfaty I., Rong S., Resau J. H., Rulong S., da Silva P. P., Vande Woude G. F. The Met proto-oncogene mesenchymal to epithelial cell conversion. Science. 1994 Jan 7;263(5143):98–101. doi: 10.1126/science.7505952. [DOI] [PubMed] [Google Scholar]
  27. Vogel W., Lammers R., Huang J., Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. 1993 Mar 12;259(5101):1611–1614. doi: 10.1126/science.7681217. [DOI] [PubMed] [Google Scholar]
  28. Weidner K. M., Arakaki N., Hartmann G., Vandekerckhove J., Weingart S., Rieder H., Fonatsch C., Tsubouchi H., Hishida T., Daikuhara Y. Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7001–7005. doi: 10.1073/pnas.88.16.7001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Weidner K. M., Behrens J., Vandekerckhove J., Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells. J Cell Biol. 1990 Nov;111(5 Pt 1):2097–2108. doi: 10.1083/jcb.111.5.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weidner K. M., Sachs M., Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 1993 Apr;121(1):145–154. doi: 10.1083/jcb.121.1.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zarnegar R., Michalopoulos G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 1989 Jun 15;49(12):3314–3320. [PubMed] [Google Scholar]

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