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The Role of Phosphatidylinositol 3-Kinase and the Mitogen-Activated Protein Kinases in Insulin-Like Growth Factor-I-Mediated Effects in Vascular Endothelial Cells¹

Center for Endocrinology, Metabolism, and Molecular Medicine (W.L., W.L.L), and Robert H. Lurie Cancer Center (Y.L.), Department of Medicine, Northwestern University Medical School and Veterans Affairs Chicago Healthcare System, Lakeside Division, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: William L. Lowe, Jr., M.D., Center for Endocrinology, Metabolism, and Molecular Medicine, Tarry 15–703, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: wlowe{at}nwu.edu

Despite an improved understanding of the molecular mechanisms of insulin-like growth factor-I (IGF-I) signaling and the recognition that IGF-I mediates many effects in endothelial cells, some of which may be important for atherosclerosis, little is known about the signal transduction pathways that mediate the effects of IGF-I in endothelial cells. To that end, we examined the signaling pathways activated by IGF-I in endothelial cells and their contribution to IGF-I-stimulated endothelial cell migration and nuclear factor (NF)-B-dependent transcription. Treatment of bovine pulmonary artery endothelial cells (PAEC) with IGF-I activated the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1/2 and ERK5. In contrast, IGF-I had no effect on either c-Jun amino-terminal kinase or p38 kinase activity. IGF-I also activated phosphatidylinositol (PI) 3-kinase, as reflected by increased phosphorylation of Akt. There was no evidence of cross-talk between the ERK and PI 3-kinase pathways in PAEC. In PAEC transiently transfected with pTK81-NFB-Luc, which contained four copies of the NF-B DNA binding site 5' to a minimal promoter and the luciferase gene, treatment with 50 ng/ml IGF-I increased luciferase activity 1.8-fold. Inhibition of ERK activity using PD98059 and PI 3-kinase activity with LY 294002 abrogated the induction of NF-B-dependent transcription by IGF-I, suggesting that both pathways contribute to the effect of IGF-I on NF-Bdependent transcription. In contrast to the effect of tumor necrosis factor- on NF-B activation, Western blot analyses demonstrated that IGF-I had no effect on IB phosphorylation and degradation or nuclear translocation and DNA binding of NF-B. These data suggest a direct of effect of IGF-I on nuclear NF-B. IGF-I also increased endothelial cell migration approximately 2-fold, as demonstrated using a Boyden chamber apparatus. IGF-I-induced endothelial cell migration was inhibited, in part, by LY 294002 but not PD98059. Together, these studies demonstrate that IGF-I activates multiple signaling pathways in endothelial cells with little evidence for cross-talk between the pathways. Moreover, these pathways appear to mediate both overlapping and distinct effects in that activation of both PI 3-kinase and the ERKs contributed to the stimulation of NF-B-dependent transcription by IGF-I, whereas only PI 3-kinase mediated IGF-I-stimulated endothelial cell migration.

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