Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations

James C. Byrd, Gayathri R. Devi, Angus T. De Souza, Randy L. Jirtle, Richard G MacDonald

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Abstract

The insulin-like growth factor II/mannose 6-phosphate receptor (IGF2R) carries out multiple regulatory and transport functions, and disruption of IGF2R function has been implicated as a mechanism to increase cell proliferation. Several missense IGF2R mutations have been identified in human cancers, including the following amino acid substitutions occurring in the extracyto-plasmic domain of the receptor: Cys-1262 → Ser, Gln1445 → His, Gly-1449 → Val, Gly-1464 → Glu, and Ile-1572 → Thr. To determine what effects these mutations have on IGF2R function, mutant and wild-type FLAG epitope-tagged IGF2R constructs lacking the transmembrane and cytoplasmic domains were characterized for binding of insulin-like growth factor (IGF)-II and a mannose 6-phosphate-bearing pseudoglycoprotein termed PMP-BSA (where PMP is pentamannose phosphate and BSA is bovine serum albumin). The Ile-1572 → Thr mutation eliminated IGF-II binding while not affecting PMP-BSA binding. Gly-1449 → Val and Cys-1262 → Ser each showed 30-60% decreases in the number of sites available to bind both 125I-IGF-II and 125I-PMP- BSA. In addition, the Gln-1445 → His mutant underwent a time-dependent loss of IGF-II binding, but not PMP-BSA binding, that was not observed for wild type. In all, four of the five cancer-associated mutants analyzed demonstrated altered ligand binding, providing further evidence that loss of IGF2R function is characteristic of certain cancers.

Original languageEnglish (US)
Pages (from-to)24408-24416
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number34
DOIs
StatePublished - Aug 20 1999

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IGF Type 2 Receptor
Insulin-Like Growth Factor II
Missense Mutation
Ligands
Neoplasms
Bearings (structural)
Mutation
Cell proliferation
Amino Acid Substitution
Bovine Serum Albumin
Epitopes
Substitution reactions
Cell Proliferation
Amino Acids
pentamannosyl phosphate substituted bovine serum albumin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations. / Byrd, James C.; Devi, Gayathri R.; De Souza, Angus T.; Jirtle, Randy L.; MacDonald, Richard G.

In: Journal of Biological Chemistry, Vol. 274, No. 34, 20.08.1999, p. 24408-24416.

Research output: Contribution to journalArticle

Byrd, James C. ; Devi, Gayathri R. ; De Souza, Angus T. ; Jirtle, Randy L. ; MacDonald, Richard G. / Disruption of ligand binding to the insulin-like growth factor II/mannose 6-phosphate receptor by cancer-associated missense mutations. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 34. pp. 24408-24416.
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