title: TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells.
abstract: 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.
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia. lyn.schedlich@sydney.edu.au
authors.forename: Lynette J
authors.initials: LJ
authors.lastname: Schedlich
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Yenson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D012516:Osteosarcoma / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D010768:Phosphoserine; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases
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