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Inducible and Reversible Dominant-negative (DN) Protein Inhibition
08:35

Inducible and Reversible Dominant-negative (DN) Protein Inhibition

Published on: January 7, 2019

Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer

Jodi L Kreiling1, Michelle A Montgomery, Joseph R Wheeler

  • 1Department of Chemistry, University of Nebraska at Omaha, Omaha, NE 68198, USA.

The FEBS Journal
|June 12, 2012
PubMed

Insights

Cancer-associated mutations in the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) can disrupt normal receptor function. Truncated M6P/IGF2R variants reduce the availability of full-length tumor suppressor receptors, potentially promoting cancer.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is crucial for ligand binding and internalization.
  • M6P/IGF2R functions as a tumor suppressor gene, and its alterations are implicated in various cancers.

Purpose of the Study:

  • To investigate the dominant-negative effects of two cancer-associated M6P/IGF2R truncation mutations (in repeats 9 and 14).
  • To determine if truncated M6P/IGF2R variants interfere with wild-type receptor function via heterodimer interference.

Main Methods:

  • Co-expression of truncated M6P/IGF2R mutants (Rep9F, Rep14F) with full-length M6P/IGF2R.
  • Immunoprecipitation to confirm heterodimer formation.
  • Quantification of full-length M6P/IGF2R levels in cell lysates and plasma membranes.
  • Assessment of degradation pathways (proteasomal, lysosomal) and proteolytic cleavage.

Main Results:

  • Heterodimeric complexes formed between full-length M6P/IGF2Rs and truncated Rep9F/Rep14F mutants.
  • Increased expression of Rep9F or Rep14F led to decreased levels of full-length M6P/IGF2R in cells and on the plasma membrane.
  • Loss of full-length M6P/IGF2R was attributed to increased proteolytic cleavage and ectodomain release, not enhanced degradation.
  • This cleavage mechanism was inhibited by metal ion chelators.

Conclusions:

  • Cancer-associated M6P/IGF2R truncation mutants exhibit dominant-negative effects by reducing the availability of functional full-length receptors.
  • These mutants may contribute to tumorigenesis by impairing the tumor-suppressive functions of M6P/IGF2R, such as binding and internalizing IGF-II.

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