Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
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.
转化生长因子-β (TGF-β) 和胰岛素样生长因子 (IGFs) 启动的信号通路在骨肉瘤细胞生长中非常重要。我们研究了内源性 IGF 结合蛋白-3 (IGFBP-3) 在调节 TGF-β 受体和 I 型 IGF 受体 (IGF1R) 信号通路之间串扰中的作用，在 MG-63 骨肉瘤细胞中。TGF-β1 间接激活 Ras/Raf/MAPK 通路，并诱导 IGFBP-3 的表达，IGFBP-3 是 IGF1R 活性的重要调节因子。IGFBP-3 减弱了 TGF-β1 在 MG-63 细胞中对 ERK1/2 和 Akt 的激活，并抑制了 TGF-β1 诱导的细胞周期进程和增殖。IGF1R 信号的抑制阻断了 IGFBP-3 的这种作用。TGF-β1 在非受体底物位点 (Ser245/250/255) 上磷酸化 Smad2。阻断 TGF-β1 诱导的 IGFBP-3 表达增强了 pSmad2(Ser245/250/255)并增加了其核积累。这些结果表明 TGF-β1 在骨肉瘤细胞生长中起着重要作用，TGF-β1 诱导的 IGFBP-3 通过防止 IGF1R 的激活来控制细胞生长，从而在负反馈回路中发挥作用。
