Abstract
Mutations in Met have been identified in human cancer, and we have previously shown that these mutations deregulate the enzymatic activity of this tyrosine kinase receptor, thereby unleashing its oncogenic potential. Signal transduction via wild type Met has been shown to require the autophosphorylation of two tyrosine doublets; Y8,9 which functions to enhance enzymatic activity, and Y14,15 which provides docking sites for signaling molecules, and in the present investigation we examine the importance of these residues for signaling via mutationally activated Met. We find that activating mutations introduced into a membrane-spanning Met receptor circumvent the normally stringent requirement for Y8,9 phosphorylation, and do so in a largely ligand-dependent fashion. Similarly, activating mutations introduced into a constitutively dimerized cytoplasmic form of Met (i.e. Tpr-Met) facilitate its autophosphorylation and oncogenic activity in the absence of Y8,9 phosphorylation. We also find that activating mutations allow a membrane-spanning Met receptor to overcome the requirement for the Y14,15 phosphorylation in a manner which is largely ligand-independent. These findings support a model whereby activating mutations stabilize an active conformation of the Met kinase via a mechanism which can function independently of Y8,9 autophosphorylation and suggest that signaling via wild type Met and mutationally activated Met may proceed through distinct pathways.
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References
Bladt F, Reithmacher D, Isenmann S, Aguzzi A and Birchmeier C. . 1995 Nature 376: 768–771.
Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF and Aaronson SA. . 1991 Science 251: 802–804.
Cooper, CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM and Vande Woude GF. . 1984 Nature (London) 311: 29–33.
Cordon-Cardo C, Tapley P, Jing S, Nanduri V, O'Rourke E, Lamballe F, Kovary K, Klein R, Jones KR, Reichardt LF and Barbacid M. . 1991 Cell 66: 173–183.
Fantl WJ, Escobedo JA and Williams LT. . 1989 Mol. Cell. Biol. 9: 4473–4478.
Fixman ED, Fournier TM, Kamikura DM, Naujokas MA and Park M. . 1996 J. Biol. Chem. 271: 13116–13122.
Fixman ED, Holgado-Madruga M, Nguyen L, Kamikura DM, Fournier TM, Wong AJ and Park M. . 1997 J. Biol. Chem. 272: 20167–20172.
Fixman ED, Naujokas MA, Rodrigues GA, Moran MF and Park M. . 1995 Oncogene 10: 237–249.
Hanks SK. . 1991 Curr. Opin. Struc. Biol. 1: 369–383.
Jeffers M, Fiscella M, Webb CP, Anver M, Koochekpour S and Vande Woude GF. . 1998a Proc. Natl. Acad. Sci. USA 95: 14417–14422.
Jeffers M. Koochekpour S, Fiscella M, Sathyanarayana BK and Vande Woude GF. . 1998b Oncogene 17: 2691–2700.
Jeffers M, Rong S, Oskarsson M, Anver M and Vande Woude GF. . 1996a Oncogene 13: 853–861.
Jeffers M, Rong S and Vande Woude GF. . 1996b J. Mol. Med. 74: 505–513.
Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B and Vande Woude GF. . 1997a Proc. Natl. Acad. Sci. USA 94: 11445–11450.
Jeffers M, Taylor GA, Weidner KM, Omura S and Vande Woude GF. . 1997b Mol. Cell. Biol. 17: 799–808.
Klein R, Jing S, Nanduri V, O'Rourke E and Barbacid M. . 1991 Cell 65: 189–197.
Martin-Zanca D, Hughes SH and Barbacid M. . 1986 Nature 319: 743–748.
Naldini L, Vigna E, Ferracini R, Longati P, Gandino L, Prat M and Comoglio PM. . 1991a Mol. Cell. Biol. 11: 1793–1803.
Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK, Birchmeier W and Comoglio PM. . 1991b EMBO J. 10: 2867–2878.
Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG and Vande Woude GF. . 1986 Cell 45: 895–904.
Pawson T and Scott JD. . 1997 Science 278: 2075–2080.
Piao X, Paulson R, van der Geer P, Pawson T and Bernstein A. . 1996 Proc. Natl. Acad. Sci. USA 93: 14665–14669.
Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G and Comoglio PM. . 1994 Cell 77: 261–271.
Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narsimhan R and Comoglio P. . 1996 J. Biol. Chem. 271: 14119–14123.
Rodrigues GA and Park M. . 1993 Mol. Cell. Biol. 13: 6711–6722.
Rodrigues GA and Park M. . 1994 Oncogene 9: 2019–2027.
Rubin JS, Bottaro DP and Aaronson SA. . 1993 Biochim. Biophys. Acta 1155: 357–371.
Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E and Birchmeier C. . 1995 Nature (London) 373: 699–702.
Schmidt L, Duh F-M, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allilmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJM, Walter MM, Tsui L-C, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM and Zbar B. . 1997 Nat. Genet. 16: 68–73.
Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M, Schlessinger J and Hubbard SR. . 1995 Nature 373: 536–539.
Sonnenberg E, Meyer D, Weidner KM and Birchmeier C. . 1993 J. Cell Biol. 123: 223–235.
Stoker M, Gherardi E, Perryman M and Gray J. . 1987 Nature (London) 327: 239–242.
Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T and Kitamura N. . 1995 Nature (London) 373: 702–705.
Van Der Geer P and Hunter T. . 1991 Mol. Cell. Biol. 11: 4698–4709.
Weidner KM, Sachs M and Birchmeier W. . 1993 J. Cell. Biol. 121: 145–154.
Weidner KM, Sachs M, Riethmacher D and Birchmeier W. . 1995 Proc. Natl. Acad. Sci. USA 92: 2597–2601.
Weiss A and Schlessinger J. . 1998 Cell 94: 277–280.
Acknowledgements
We thank Walter Birchmeier for the wild type Trk-Met expression vector; Linda Miller, Marilyn Powers, Leo Lee, Terry Sweeney and Oscar Smith for technical support; Richard Frederickson and Allan Kane for performing the artwork and photography; and Ave Cline for manuscript preparation. Research sponsored in part by the National Cancer Institute, DHSS, under contract with ABL.
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Jeffers, M., Vande Woude, G. Activating mutations in the Met receptor overcome the requirement for autophosphorylation of tyrosines crucial for wild type signaling. Oncogene 18, 5120–5125 (1999). https://doi.org/10.1038/sj.onc.1202902
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DOI: https://doi.org/10.1038/sj.onc.1202902
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