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

Jodi L. Kreiling, Michelle A. Montgomery, Joseph R. Wheeler, Jennifer L. Kopanic, Christopher M. Connelly, Megan E. Zavorka, Jenna L. Allison, Richard G MacDonald

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II. Structured digital abstract with by (View Interaction:,) with by (View Interaction:,) Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal IGF-II binding, internalization, and degradation. Increasing expression of Rep9F or Rep14F, two cancer-associated M6P/IGF2R mutations that truncate the receptor in ectodomain repeats 9 and 14 decreased levels of full-length M6P/IGF2Rs. The effect was due to proteolytic cleavage resulting in ectodomain release and was inhibited by zinc chelators

Original languageEnglish (US)
Pages (from-to)2695-2713
Number of pages19
JournalFEBS Journal
Volume279
Issue number15
DOIs
StatePublished - Aug 1 2012

Fingerprint

IGF Type 2 Receptor
Oligomerization
Insulin-Like Growth Factor II
Cell membranes
Chelating Agents
Tumors
Availability
Ligands
Degradation
Metal ions
Zinc
Neoplasms
Genes
Cell Membrane
Mutation
Loss of Heterozygosity
Tumor Suppressor Genes
Immunoprecipitation
Metals
mannose-6-phosphate

Keywords

  • dimerization
  • dominant negative
  • ectodomain shedding
  • mannose 6-phosphate receptor
  • truncation mutants

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kreiling, J. L., Montgomery, M. A., Wheeler, J. R., Kopanic, J. L., Connelly, C. M., Zavorka, M. E., ... MacDonald, R. G. (2012). Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer. FEBS Journal, 279(15), 2695-2713. https://doi.org/10.1111/j.1742-4658.2012.08652.x

Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer. / Kreiling, Jodi L.; Montgomery, Michelle A.; Wheeler, Joseph R.; Kopanic, Jennifer L.; Connelly, Christopher M.; Zavorka, Megan E.; Allison, Jenna L.; MacDonald, Richard G.

In: FEBS Journal, Vol. 279, No. 15, 01.08.2012, p. 2695-2713.

Research output: Contribution to journalArticle

Kreiling, JL, Montgomery, MA, Wheeler, JR, Kopanic, JL, Connelly, CM, Zavorka, ME, Allison, JL & MacDonald, RG 2012, 'Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer', FEBS Journal, vol. 279, no. 15, pp. 2695-2713. https://doi.org/10.1111/j.1742-4658.2012.08652.x
Kreiling JL, Montgomery MA, Wheeler JR, Kopanic JL, Connelly CM, Zavorka ME et al. Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer. FEBS Journal. 2012 Aug 1;279(15):2695-2713. https://doi.org/10.1111/j.1742-4658.2012.08652.x
Kreiling, Jodi L. ; Montgomery, Michelle A. ; Wheeler, Joseph R. ; Kopanic, Jennifer L. ; Connelly, Christopher M. ; Zavorka, Megan E. ; Allison, Jenna L. ; MacDonald, Richard G. / Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer. In: FEBS Journal. 2012 ; Vol. 279, No. 15. pp. 2695-2713.
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KW - dimerization

KW - dominant negative

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