TGF-ß-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells.
Mol Cell Endocrinol
; 377(1-2): 56-64, 2013 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-23831640
ABSTRACT
Signaling pathways initiated by transforming growth factor-ß (TGF-ß) 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-ß receptor and type I IGF receptor (IGF1R) signaling pathways in MG-63 osteosarcoma cells. TGF-ß1 indirectly activated the Ras/Raf/MAPK pathway and induced the expression of IGFBP-3, an important regulator of IGF1R activity. IGFBP-3 attenuated TGF-ß1 activation of ERK1/2 and Akt in MG-63 cells, and inhibited TGF-ß1-induced cell cycle progression and proliferation. This effect of IGFBP-3 was blocked by inhibiting IGF1R signaling. TGF-ß1 phosphorylated Smad2 on the non-receptor substrate sites (Ser245/250/255). Blocking the TGF-ß1-induced expression of IGFBP-3 enhanced pSmad2(Ser245/250/255) and increased its nuclear accumulation. These results suggest an important role for TGF-ß1 in osteosarcoma cell growth, with the induction of IGFBP-3 by TGF-ß1 serving in a negative-feedback loop to control cell growth by preventing activation of the IGF1R.
Palavras-chave
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-ß; TGF-ß receptor; TGF-ß type I receptor; TGF-ß type II receptor; Transforming growth factor-ß; TßR; TßRI; TßRII; 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-ß; type I IGF receptor
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Osteossarcoma
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Fator de Crescimento Transformador beta
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Receptor IGF Tipo 1
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Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina
Limite:
Humans
Idioma:
En
Revista:
Mol Cell Endocrinol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Austrália