Insulin-like growth factor-II enhancement of human fibroblast growth via a nonreceptor-mediated mechanism

Cheryl A. Conover, Jay T. Clarkson, Laurie K. Bale

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Deciphering the complex interactions of the various components of the insulin-like growth factor (IGF) system [IGF-I and -II peptides, type I and II IGF receptors, and IGF-binding proteins (IGFBPs)] is important for our understanding of cell growth regulation. We report here that IGF-II can enhance IGF-I-stimulated cell proliferation independent of direct IGF-II interaction with type I or II IGF receptors. Human fibroblasts cultured in serum-free medium for 40 h were relatively resistant to the mitogenic effects of added IGF-I. However, preexposure of the cultures to low concentrations of IGF-II enhanced IGF-I action several-fold. IGF-II by itself had no stimulatory effect and did not influence [Gln3, Ala4, Tyr15, Leu16]IGF-I or insulin-stimulated DNA synthesis. IGF-II did not directly interact with type I IGF receptors, as [Leu27]IGF-II, an IGF-II analog that does not bind type I IGF receptors, could mimic IGF-II's potentiating effect. Type II IGF receptors also were not involved because 1) [Gln6, Ala7, Tyr18, Leu19, Leu27]IGF-II, an analog with normal receptor binding, had no effect; and 2) β-galactosidase, a competitive inhibitor of IGF-II receptor binding, did not influence IGF-II potentiation of IGF-I action. Enhanced cell responsiveness to IGF-I appears to be due to IGF-II-induced changes in pericellular IGFBP-3 and IGFBP-4. These data support the hypothesis that IGF-II can potentiate the action of IGF-I by disrupting the IGFBP barrier at the cell surface, thereby increasing IGF-I availability for type I IGF receptor interaction.

Original languageEnglish (US)
Pages (from-to)76-82
Number of pages7
JournalEndocrinology
Volume135
Issue number1
DOIs
StatePublished - Jul 1994

ASJC Scopus subject areas

  • Endocrinology

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