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Stimulation of Insulin-Like Growth Factor (IGF) Binding Protein-3 Synthesis by IGF-I and Transforming Growth Factor- Is Mediated by Both Phosphatidylinositol-3 Kinase and Mitogen-Activated Protein Kinase Pathways in Mammary Epithelial Cells

Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8520

Address all correspondence and requests for reprints to: Wendie S. Cohick, Ph.D., Rutgers, The State University of New Jersey, 108 Foran Hall, 59 Dudley Road, New Brunswick, New Jersey 08901-8520. E-mail: cohick{at}aesop.rugters.edu.

IGF binding protein (IGFBP)-3 is an important regulator of mammary epithelial cell (MEC) growth and can enhance the ability of both IGF-I and epidermal growth factor ligands such as TGF to stimulate MEC proliferation. Here we investigate the role of the phosphatidylinositol-3 kinase (PI3K) and MAPK pathways in the regulation of IGFBP-3 expression by IGF-I and TGF in bovine MECs. Both growth factors stimulated DNA synthesis, although IGF-I was the stronger mitogen. IGF-I and TGF also stimulated IGFBP-3 mRNA and protein levels. TGF stimulated rapid, transient activation of Akt that was maximal at 5 min and diminished by 15 min. In contrast, IGF-I-induced Akt activation was maximal between 15 and 90 min and was sustained for 6 h. Although ERK 1/2 was maximally stimulated by TGF between 5 and 15 min, IGF-I did not stimulate discernible activation of ERK 1/2. In addition, TGF but not IGF-I induced rapid phosphorylation of Shc, whereas only IGF-I activated insulin receptor substrate-1. Pretreatment with the PI3K inhibitor LY294002 or knockdown of p85 with small interfering RNA inhibited IGF-I or TGF-stimulated IGFBP-3 expression. Similarly, MAPK kinase-1 inhibitors PD98059 and U0126 each abolished TGF-stimulated increases in IGFBP-3 mRNA levels. In contrast to TGF, IGF-I retained the ability to partially increase IGFBP-3 mRNA levels in the presence of MAPK kinase-1 inhibitors, indicating that IGF-I may activate alternative substrates of the PI3K pathway that are involved in IGFBP-3 regulation. In conclusion, stimulation of IGFBP-3 mRNA levels by mitogens is regulated through both the PI3K and MAPK pathways in bovine MECs.

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