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Cripto-1 Induces Phosphatidylinositol 3'-Kinase-dependent Phosphorylation of AKT and Glycogen Synthase Kinase 3ß in Human Cervical Carcinoma Cells

National Cancer Institute, Laboratory of Tumor Immunology and Biology, Tumor Growth Factor Section [A. D. E., C. W., B. W-J., I. M-L., C. B., D. S. S.] and National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch [S. F.], National Institutes of Health, Bethesda, Maryland 20892; Free University Berlin, Medical Center Benjamin Franklin, Department of Obstetrics and Gynecology, 12200 Berlin, Germany [A. D. E., H. K. W.]; Faculty of Engineering, Department of Bioscience and Biotechnology, Okayama University, Okayama 700-8530, Japan [M. S.]; and Walter Reed Army Institute of Research, Department of Molecular Pathology, Washington, D.C. 20307 [M. D. S.]

Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3ß (GSK-3ß)-dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3ß. Phosphorylation of AKT and GSK-3ß by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3ß.

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