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Transmembrane Domain Oligomerization Propensity determined by ToxR Assay
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The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the

Dogus Murat Altintas1, Simona Gallo2,3, Cristina Basilico2

  • 1IFOM, FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milano, Italy.

International Journal of Molecular Sciences
|October 27, 2022
PubMed

Insights

The MET oncogene

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The MET oncogene encodes a tyrosine kinase receptor crucial in cell signaling.
  • The function of its conserved PSI domain remains unknown.
  • The PSI domain contains CXXC motifs, characteristic of protein disulfide isomerases (PDIs).

Purpose of the Study:

  • To investigate the functional role of the MET PSI domain.
  • To determine if the MET PSI domain possesses enzymatic activity.
  • To elucidate the PSI domain's involvement in MET receptor maturation and signaling.

Main Methods:

  • In vitro enzymatic activity assay using scrambled oxidized RNAse.
  • Antibody-mediated inhibition of PSI domain activity.
  • Analysis of MET precursor cleavage, chain maturation, and subcellular localization (Golgi apparatus).
  • Assessment of MET phosphorylation (constitutive) and downstream signaling (AKT, MAPK).
  • Evaluation of biological responses to hepatocyte growth factor (HGF), including cell growth and epithelial-to-mesenchymal transition (EMT).

Main Results:

  • The MET extracellular domain exhibits protein disulfide isomerase (PDI) activity, confirmed by in vitro assays and abolished by PSI domain antibodies.
  • Deletion or mutation of CXXC motifs in the PSI domain impairs MET precursor cleavage and maturation of disulfide-linked α and β chains.
  • The uncleaved MET precursor accumulates in the Golgi apparatus and shows constitutive phosphorylation but lacks downstream signal transduction (AKT, MAPK).
  • Biological functions mediated by hepatocyte growth factor (HGF), such as cell growth and EMT, are significantly reduced.

Conclusions:

  • The MET PSI domain is a functional entity with protein disulfide isomerase (PDI) activity.
  • This PDI activity is essential for the proper maturation, processing, and surface expression of the MET receptor.
  • The PSI domain's function is critical for MET-mediated biological responses, including cell growth and epithelial-to-mesenchymal transition.
Keywords:
Golgi apparatusMETPSI domainoncogeneprotein disulfide isomeraseprotein maturation

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