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  • Original Paper
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Differential requirement of the last C-terminal tail of Met receptor for cell transformation and invasiveness

Oncogene volume 20, pages 5493–5502 (2001)Cite this article

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

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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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  1. Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Str. Prov. 142, Km 3.95, Candiolo, 10060, Italy

    Philippe Gual, Silvia Giordano, Sergio Anguissola & Paolo Maria Comoglio

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  1. Philippe Gual
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  2. Silvia Giordano
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  4. Paolo Maria Comoglio
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Correspondence to Silvia Giordano.

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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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