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NTSR1 glycosylation and MMP dependent cleavage generate three distinct forms of the protein

Fotine Libanje1, Raphael Delille2, Pamela A Young2

  • 1Translational Biomarkers and Pharmacology, IPSEN Innovation, Les Ulis, France. Fotine.libanje@gmail.com.

Scientific Reports
|March 23, 2023
PubMed

Insights

Understanding Neurotensin Receptor 1 (NTSR1) protein forms is key for developing NTSR1-targeted cancer therapies. The NTSR1-low form is most abundant in tumors, highlighting its therapeutic relevance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Neurotensin Receptor 1 (NTSR1) is a target for anti-cancer therapies due to its abnormal expression in cancer cells.
  • Therapeutic success depends on NTSR1 protein availability and accessibility, necessitating a deeper understanding of its biology.

Purpose of the Study:

  • To investigate the different forms of NTSR1 protein expressed in tumoral and non-tumoral cells.
  • To elucidate the mechanisms regulating NTSR1 protein processing and localization.
  • To determine the relevance of NTSR1 protein forms in cancer pathology.

Main Methods:

  • Studied NTSR1 protein expression in cells with exogenous and endogenous expression.
  • Utilized biochemical assays to identify and characterize different NTSR1 protein forms.
  • Investigated the role of matrix metalloproteinases (MMPs) and Neurotensin (NTS) ligand in NTSR1 processing.
  • Analyzed NTSR1 protein localization, internalization, and degradation pathways.

Main Results:

  • Identified three distinct NTSR1 protein forms: NTSR1-high (glycosylated), NTSR1-low (N-terminally cleaved, de-glycosylated), and NTSR1-LP (predicted size).
  • Demonstrated that MMPs cleave NTSR1-high to NTSR1-low, a process enhanced by NTS.
  • Showed NTS induces internalization of plasma membrane NTSR1 and proteasomal degradation of NTSR1-low.
  • Found NTSR1-low to be the predominant form in tumoral cells and PDAC xenografts.

Conclusions:

  • NTSR1 protein exists in multiple forms with distinct processing pathways.
  • The NTSR1-low form is significantly abundant in tumors, indicating its pathological relevance.
  • These findings provide crucial insights and tools for developing NTSR1-targeting anti-tumoral therapies.

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