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

P. Gual, S. Giordano, S. Anguissola, P. M. Comoglio

Research output: Contribution to journalArticlepeer-review

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-point regulation of Met enzymatic activity by insertion of a 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 hut also for regulation of receptor enzymatic activity.

Original languageEnglish
Pages (from-to)5493-5502
Number of pages10
JournalOncogene
Volume20
Issue number39
DOIs
Publication statusPublished - Sep 6 2001

Keywords

  • C-terminal domain
  • Cell transformation
  • Invasiveness
  • Kinase activity
  • Met
  • Regulatory domain

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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