Abstract
Biological responses to Hepatocyte Growth Factor are mediated by the tyrosine kinase receptor encoded by the Met oncogene. Under physiological conditions, Met triggers a multi-step genetic program called ‘invasive growth’ including cell-dissociation, invasion of extracellular matrices and growth. When constitutively activated, Met can induce cell transformation and metastasis. Phosphorylation of two docking tyrosines in the receptor tail is essential for all biological responses. To investigate the role of the C-terminal part of Met, we have generated mutants lacking either the last 26 or 47 amino acids. As expected, mutants lacking the docking sites fail to mediate cell transformation and invasion. Interestingly, while Met Δ26 can mediate invasion, its transforming ability is severely impaired. Moreover, the lack of the last 26 amino acids strongly reduces Met ability to phosphorylate substrates in vitro and in vivo. These data indicate that the last 26 amino acids are required to confer the kinase its full enzymatic activity, which is critical for cell transformation but dispensable for invasive properties. Finally, we also show that up-regulation of Met enzymatic activity by insertion of a point mutation in the kinase domain (M1250T) overcomes the regulatory role played by the last 26 amino acids of the tail. It is concluded that the C-terminal domain of Met is crucial not only for recruitment of transducers but also for regulation of receptor enzymatic activity.
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Abbreviations
- HGF:
-
hepatocyte growth factor
- GRB-2:
-
growth factor receptor-bound protein 2
- Gab1:
-
GRB2 associated binder-1
- PI 3 kinase:
-
phosphoinositide 3 kinase
- STAT:
-
signal transducer and activator of the transcription
- SHPTP:
-
SH2 containing Phosphotyrosine phosphatase
- SHC:
-
Src homology/collagen
- SH2:
-
Src homology 2
- p85:
-
the 85 kDa regulatory subunit of PI 3 kinase
- pr:
-
precursor
- GST:
-
glutathione S-transferase
References
Asai N, Murakami H, Iwashita T, Takahashi M . 1996 J. Biol. Chem. 271: 17644–17649
Bardelli A, Longati P, Gramaglia D, Stella MC, Comoglio PM . 1997 Oncogene 18: 3103–3111
Bardelli A, Longati P, Gramaglia D, Basilico C, Tamagnone L, Giordano S, Ballinari D, Michieli P, Comoglio PM . 1998 Proc. Natl. Acad. Sci. USA 95: 14379–14383
Bardelli A, Longati P, Williams TA, Benvenuti S, Comoglio PM . 1999 J. Biol. Chem. 274: 29274–29281
Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C . 1995 Nature 376: 768–771
Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM . 1998 Nature 391: 285–288
Borrello MG, Smith DP, Pasini B, Bongarzone I, Greco A, Lorenzo MJ, Arighi E, Miranda C, Eng C, Alberti L, Bocciardi R, Mondellini P, Scopsi L, Romeo G, Ponder B, Pierotti M . 1995 Oncogene 11: 2419–2427
Comoglio PM, Tamagnone L, Boccaccio C . 1999 Exp. Cell. Res. 253: 88–99
Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, Vande Woude GF . 1984 Nature 311: 29–33
Di Renzo MF, Olivero M, Ferro S, Prat M, Bongarzone I, Pilotti S, Belfiore A, Costantino A, Vigneri R, Pierotti MA, Comoglio PM . 1992 Oncogene 7: 2549–2553
Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, Sismondi P, Comoglio PM . 1994 Int. J. Cancer 58: 658–662
Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M, Comoglio PM . 1995 Oncogene 10: 739–749
Ferracini R, Longati P, Naldini L, Vigna E, Comoglio PM . 1991 J. Biol. Chem. 266: 19558–19564
Fixman ED, Holgado-Madruga M, Nguyen L, Kamikura DM, Fournier TM, Wong AJ, Park M . 1997 J. Biol. Chem. 272: 20167–20172
Furge KA, Zhang YW, Vande Woude GF . 2000 Oncogene 19: 5582–5589
Gandino L, Di Renzo MF, Giordano S, Bussolino F, Comoglio PM . 1990 Oncogene 5: 721–725
Gandino L, Longati P, Medico E, Prat M, Comoglio PM . 1994 J. Biol. Chem. 269: 1815–1820
Garcia-Guzman M, Dolfi F, Zeh K, Vuori K . 1999 Oncogene 18: 7775–7786
Giordano S, Maffe A, Williams TA, Artigiani S, Gual P, Bardelli A, Basilico C, Michieli P, Comoglio PM . 2000 FASEB J. 14: 399–406
Graziani A, Gramaglia D, Cantley LC, Comoglio PM . 1991 J. Biol. Chem. 266: 22087–22090
Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hopperner JW, van Amstel HK, Romeo G, Lips CJM, Buys CHCM . 1994 Nature 367: 375–376
Hubbard SR . 1997 EMBO J. 16: 5572–5581
Hubbard SR, Wei L, Ellis L, Hendrickson WA . 1994 Nature 372: 746–754
Itoh M, Yoshida Y, Nishida K, Narimatsu M, Hibi M, Hirano T . 2000 Mol. Cell. Biol. 20: 3695–3704
Iwashita T, Asai N, Murakami H, Matsuyama M, Takahashi M . 1996 Oncogene 12: 481–487
Korhonen JM, Said FA, Wong AJ, Kaplan DR . 1999 J. Biol. Chem. 274: 37307–37314
Longati P, Bardelli A, Ponzetto C, Naldini L, Comoglio PM . 1994 Oncogene 9: 49–57
Maina F, Casagranda F, Audero E, Simeone A, Comoglio PM, Klein R, Ponzetto C . 1996 Cell 87: 531–542
Maritano D, Accornero P, Bonifaci N, Ponzetto C . 2000 Oncogene 19: 1354–1361
Medico E, Mongiovì AM, Huff J, Jelinek MA, Follenzi A, Gaudino G, Parsons JT, Comoglio PM . 1996 Mol. Biol. Cell 7: 495–504
Montesano R, Matsumoto K, Nakamura T, Orci L . 1991 Cell 67: 901–908
Naldini L, Vigna E, Ferracini R, Longati P, Gandino L, Prat M, Comoglio PM . 1991 Mol. Cell. Biol. 11: 1793–1803
Park CY, Hayman MJ . 1999 J. Biol. Chem. 274: 7583–7590
Park M, Dean M, Cooper CS, Schmidt M, O'Brien SJ, Blair DG, Vande Woude GF . 1986 Cell 45: 895–904
Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG, Comoglio PM . 1995 Oncogene 10: 1631–1638
Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM . 1994 Cell 77: 261–271
Ponzetto C, Zhen Z, Audero E, Maina F, Bardelli A, Basile ML, Giordano S, Narsimhan R, Comoglio PM . 1996 J. Biol. Chem. 271: 14119–14123
Rodrigues GA, Park M . 1993 Mol. Cell. Biol. 13: 6711–6722
Rodrigues GA, Park M, Schlessinger J . 1997 EMBO J. 16: 2634–2645
Rong S, Segal S, Anver M, Resau JH, Vande Woude GF . 1994a Proc. Natl. Acad. Sci. USA 91: 4731–4735
Rong S, Vande Woude GF . 1994b Cold Spring Harb. Symp. Quant. Biol. 59: 629–636
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH, Di Fiore PP . 1995 Science 267: 381–383
Santoro MM, Collesi C, Grisendi S, Gaudino G, Comoglio PM . 1996 Mol. Cell. Biol. 16: 7072–7083
Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W . 2000 J. Cell. Biol. 149: 1419–1432
Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C . 1995 Nature 373: 699–702
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Zbar B . 1997 Nat. Genet. 16: 68–73
Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, Walther M, Linehan WM, Zbar B . 1998 Cancer Res. 58: 1719–1722
Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, Kitamura N . 1995 Nature 373: 702–705
Villa-Moruzzi E, Lapi S, Prat M, Gaudino G, Comoglio PM . 1993 J. Biol. Chem. 268: 18176–18180
Weidner KM, DiCesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . 1996 Nature 384: 173–176
Williams TA, Longati P, Pugliese L, Gual P, Bardelli A, Michieli P . 1999 J. Cell Physiol. 181: 507–514
Xiao ZQ, Chen YQ, Wang MH . 2000 Biochem. Biophys. Res. Commun. 267: 669–675
Zhen Z, Giordano S, Longati P, Medico E, Campiglio M, Comoglio PM . 1994 Oncogene 9: 1691–1697
Acknowledgements
We are grateful to Dr W Birchmeier for mouse Gab1 cDNA and to S Corso for providing the Tpr-MetM1250T mutant. The excellent technical assistance of L Palmas, R Albano and G Petruccelli is gratefully acknowledged. We thank Antonella Cignetto for secretarial help and Elaine Wright for editing the manuscript. This work was supported by BIOMED EC grant no BMH4-CT98-3852 and by Italian Association for Cancer Research (AIRC) to PM Comoglio and by MURST COFIN 1999 to S Giordano. P Gual is supported by Marie Curie TMR fellowships contract no ERBFMBICT 983138.
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Gual, P., Giordano, S., Anguissola, S. et al. Differential requirement of the last C-terminal tail of Met receptor for cell transformation and invasiveness. Oncogene 20, 5493–5502 (2001). https://doi.org/10.1038/sj.onc.1204713
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DOI: https://doi.org/10.1038/sj.onc.1204713
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