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The PSI Domain of the MET Oncogene Encodes a Functional Disulfide Isomerase Essential for the Maturation of the Receptor Precursor. | LitMetric

AI Article Synopsis

  • The MET oncogene's tyrosine kinase receptor has an extracellular domain called PSI, which has been previously unexplored in terms of function despite being evolutionarily conserved.
  • Recent experiments reveal that the MET extracellular PSI domain exhibits disulfide isomerase activity, crucial for the maturation process of the MET precursor protein into its active forms, which are involved in signaling pathways.
  • Mutations in the PSI domain hinder the cleavage and maturation of the MET protein, leading to its accumulation in the Golgi apparatus and preventing essential biological processes triggered by its ligand, Hepatocyte Growth Factor (HGF).

Article Abstract

The tyrosine kinase receptor encoded by the MET oncogene has been extensively studied. Surprisingly, one extracellular domain, PSI, evolutionary conserved between plexins, semaphorins, and integrins, has no established function. The MET PSI sequence contains two CXXC motifs, usually found in protein disulfide isomerases (PDI). Using a scrambled oxidized RNAse enzymatic activity assay in vitro, we show, for the first time, that the MET extracellular domain displays disulfide isomerase activity, abolished by PSI domain antibodies. PSI domain deletion or mutations of CXXC sites to AXXA or SXXS result in a significant impairment of the cleavage of the MET 175 kDa precursor protein, abolishing the maturation of α and β chains, of, respectively, 50 kDa and 145 kDa, disulfide-linked. The uncleaved precursor is stuck in the Golgi apparatus and, interestingly, is constitutively phosphorylated. However, no signal transduction is observed as measured by AKT and MAPK phosphorylation. Consequently, biological responses to the MET ligand-hepatocyte growth factor (HGF)-such as growth and epithelial to mesenchymal transition, are hampered. These data show that the MET PSI domain is functional and is required for the maturation, surface expression, and biological functions of the MET oncogenic protein.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604360PMC
http://dx.doi.org/10.3390/ijms232012427DOI Listing

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