Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

Elisa Vigna, Daniela Gramaglia, Paola Longati, Alberto Bardelli, Paolo M. Comoglio

Research output: Contribution to journalArticlepeer-review

Abstract

TPR-MET, a transforming counterpart of the c-MET proto-oncogene detected in experimental and human cancer, results from fusion of the MET kinase domain with a dimerization motif encoded by TPR. In this rearrangement the exons encoding the Met extracellular, transmembrane and juxtamembrane domains are lost. The juxtamembrane domain has been suggested to be a regulatory region endowed with negative feedback control. To understand whether its absence is critical for the generation of the Tpr-Met transforming potential, we produced a chimeric molecule (Tpr-juxtaMet) with a conserved juxtamembrane domain. The presence of the domain (aa 962-1009) strongly inhibited Tpr-Met dependent cell transformation. Cell proliferation, anchorage-independent growth, motility and invasion were also impaired. The enzymatic behavior of Tpr-Met and Tpr-juxtaMet was the same, while Tpr-juxtaMet ability to associate cytoplasmic signal transducers and to elicit downstream signaling was severely impaired. These data indicate that the presence of the juxtamembrane domain counterbalances the Tpr-Met transforming potential and therefore the loss of the exon encoding the juxtamembrane domain is crucial in the generation of the active TPR-MET oncogene.

Original languageEnglish
Pages (from-to)4275-4281
Number of pages7
JournalOncogene
Volume18
Issue number29
DOIs
Publication statusPublished - Jul 22 1999

Keywords

  • MET-receptor
  • Tpr-Met
  • Transformation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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