Functional collaboration of insulin-like growth factor-1 receptor (IGF-1R), but not insulin receptor (IR), with acute GH signaling in mouse calvarial cells

Academic Article

Abstract

  • GH signals through the GH receptor (GHR), a cytokine receptor linked to Janus kinase 2 (JAK2). GH activates signal transducer and activator of transcription 5 (STAT5), causing expression of genes including IGF-I. IGF-I binds IGF-I receptor (IGF-IR), a heterotetrameric (α2-β2) tyrosine kinase growth factor receptor similar to insulin receptor (IR). In addition to this GH -> GHR -> IGF-I >- IGF-IR pathway, GH induces a complex including GHR, JAK2, and IGF-IR and deletion of floxed IGF-1R in primary murine calvarial cells with Cre-recombinase-expressing adenovirus (Ad-Cre) desensitizes cells to GH for STAT5 activation and IGF-I mRNA accumulation. Diminished GH-induced STAT5 phosphorylation in Ad-Cre-treated cells is rescued by adenoviruses encoding either IGF-IR or IGF-IR lacking the β-chain intracellular domain. Reasoning that IGF-IR's extracellular portion (α or extracellular β) mediates functional interaction with GH signaling, we pursued reconstitution studies. Although structurally related to IGF-IR, IR expressed adenovirally did not rescue GH-induced STAT5 phosphorylation in Ad-Cre-treated cells. We thus created chimeras, swapping homologous IR extracellular regions into IGF-IR. IR and IGF-IR possess N-terminal L1, cysteine-rich (CR), and L2 α-chain domains. We created Ad-IGF-IR/IR-L1 and Ad-IGF-IR/IR-L1-CR-L2, in which L1 alone or L1, CR, and L2 of IR replace corresponding IGF-IR regions, respectively. Ad-IGF-IR/IR-L1, but not Ad-IGF-IR/IR-L1-CR-L2, rescued GH-induced STAT5 phosphorylation in Ad-Cre-treated cells. Additionally, medium containing a soluble IGF-IR (including only L1-CR-L2) dampened GH-induced STAT5 phosphorylation in calvarial cells and two other GH-responsive cell lines. Thus, an extracellular determinant(s), likely in CR-L2, specifically allows IGF-IR to collaborate with GHR and JAK2 for robust GH-induced acute STAT5 phosphorylation. Copyright © 2014 by the Endocrine Society.
  • Published In

  • Endocrinology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Gan Y; Paterson AJ; Zhang Y; Jiang J; Frank SJ
  • Start Page

  • 1000
  • End Page

  • 1009
  • Volume

  • 155
  • Issue

  • 3