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

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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