TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells

Mol Cell Endocrinol. 2013 Sep 5;377(1-2):56-64. doi: 10.1016/j.mce.2013.06.033. Epub 2013 Jul 2.


Signaling pathways initiated by transforming growth factor-β (TGF-β) and insulin-like growth factors (IGFs) are important in osteosarcoma cell growth. We have investigated a role for endogenous IGF binding protein-3 (IGFBP-3) in mediating cross-talk between TGF-β receptor and type I IGF receptor (IGF1R) signaling pathways in MG-63 osteosarcoma cells. TGF-β1 indirectly activated the Ras/Raf/MAPK pathway and induced the expression of IGFBP-3, an important regulator of IGF1R activity. IGFBP-3 attenuated TGF-β1 activation of ERK1/2 and Akt in MG-63 cells, and inhibited TGF-β1-induced cell cycle progression and proliferation. This effect of IGFBP-3 was blocked by inhibiting IGF1R signaling. TGF-β1 phosphorylated Smad2 on the non-receptor substrate sites (Ser245/250/255). Blocking the TGF-β1-induced expression of IGFBP-3 enhanced pSmad2(Ser245/250/255) and increased its nuclear accumulation. These results suggest an important role for TGF-β1 in osteosarcoma cell growth, with the induction of IGFBP-3 by TGF-β1 serving in a negative-feedback loop to control cell growth by preventing activation of the IGF1R.

Keywords: EGF; HGF; IGF; IGF binding protein-3; IGF1R; IGF1R KI; IGF1R kinase inhibitor; IGFBP-3; Insulin-like growth factor; Insulin-like growth factor binding protein-3; MAPK; Osteosarcoma; PI3-K; R-Smads; RNA interference; RNAi; SAPK/JNK; Signaling; TGF-β; TGF-β receptor; TGF-β type I receptor; TGF-β type II receptor; Transforming growth factor-β; TβR; TβRI; TβRII; c-Jun N-terminal kinase; epidermal growth factor; hepatocyte growth factor; insulin-like growth factor; mitogen activated protein kinase; phosphoinositide 3-kinase; receptor-activated Smads; transforming growth factor-β; type I IGF receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Osteosarcoma / enzymology
  • Osteosarcoma / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Receptor Cross-Talk / drug effects
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects*
  • Smad2 Protein / metabolism
  • Substrate Specificity / drug effects
  • Transforming Growth Factor beta / pharmacology*


  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta
  • Phosphoserine
  • Receptor, IGF Type 1
  • Extracellular Signal-Regulated MAP Kinases