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HORMONES AND SIGNALING

IGFBP-3 activates TGF- receptors and directly inhibits growth in human intestinal smooth muscle cells

Departments of Medicine and Physiology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298

Submitted 9 January 2004 ; accepted in final form 26 May 2004

We have shown that human intestinal smooth muscle cells produce IGF-I and IGF binding protein-3 (IGFBP-3). Endogenous IGF-I acts in autocrine fashion to stimulate growth of these cells. IGFBP-3 inhibits the binding of IGF-I to its receptor and thereby inhibits IGF-I-stimulated growth. In several carcinoma cell lines and some normal cells, IGFBP-3 regulates growth independently of IGF-I. Two mechanisms for this effect have been identified: IGFBP-3 can directly activate transforming growth factor- (TGF-) receptors or it can undergo direct nuclear translocation. The aim of the present study was to determine whether IGFBP-3 acts independently of IGF-I and to characterize the mechanisms mediating this effect in human intestinal smooth muscle cells. The direct effects of IGFBP-3 were determined in the presence of an IGF-I receptor antagonist to eliminate its IGF-I-dependent effects. Affinity labeling of TGF- receptors (TGF-RI, TGF-RII, and TGF-RV) with ¹²⁵I-labeled TGF-1 showed that IGFBP-3 displaced binding to TGF-RII and TGF-RV in a concentration-dependent fashion. IGFBP-3 stimulated TGF-RII-dependent serine phosphorylation (activation) of both TGF-RI and of its primary substrate, Smad2(Ser^465/467). IGFBP-3 also caused IGF-I-independent inhibition of basal [³H]thymidine incorporation. The effects of IGFBP-3 on Smad2 phosphorylation and on smooth muscle cell proliferation were independent of TGF-1 and were abolished by transfection of Smad2 siRNA. Immunoneutralization of IGFBP-3 increased basal [³H]thymidine incorporation, implying that endogenous IGFBP-3 inhibits proliferation. We conclude that endogenous IGFBP-3 directly inhibits proliferation of human intestinal smooth muscle cells by activation of TGF-RI and Smad2, an effect that is independent of its effect on IGF-I-stimulated growth.

insulin-like growth factor-I; Smad2; short interfering RNA

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