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

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• 作者：Lynette J. Schedlich ; Vanessa M. Yenson ; Robert C. Baxter
• 关键词：TGF-¦Â ; transforming growth factor-¦Â ; IGF ; insulin-like growth factor ; IGFBP-3 ; IGF binding protein-3 ; T¦ÂR ; TGF-¦Â receptor ; IGF1R ; type I IGF receptor ; T¦ÂRII ; TGF-¦Â type II receptor ; T¦ÂRI ; TGF-¦Â type I receptor ; R-Smads ; receptor-activated Smads ; M
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2013
• 出版时间：5 September, 2013
• 年：2013
• 卷：377
• 期：1-2
• 页码：56-64
• 全文大小：1298 K

文摘

Signaling pathways initiated by transforming growth factor-¦Â (TGF-¦Â) 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-¦Â receptor and type I IGF receptor (IGF1R) signaling pathways in MG-63 osteosarcoma cells. TGF-¦Â1 indirectly activated the Ras/Raf/MAPK pathway and induced the expression of IGFBP-3, an important regulator of IGF1R activity. IGFBP-3 attenuated TGF-¦Â1 activation of ERK1/2 and Akt in MG-63 cells, and inhibited TGF-¦Â1-induced cell cycle progression and proliferation. This effect of IGFBP-3 was blocked by inhibiting IGF1R signaling. TGF-¦Â1 phosphorylated Smad2 on the non-receptor substrate sites (Ser245/250/255). Blocking the TGF-¦Â1-induced expression of IGFBP-3 enhanced pSmad2(Ser245/250/255) and increased its nuclear accumulation. These results suggest an important role for TGF-¦Â1 in osteosarcoma cell growth, with the induction of IGFBP-3 by TGF-¦Â1 serving in a negative-feedback loop to control cell growth by preventing activation of the IGF1R.