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Elevated Inorganic Phosphate Stimulates Akt-ERK1/2-Mnk1 Signaling in Human Lung Cells

Laboratory of Toxicology, College of Veterinary Medicine and BK21 Program for Veterinary Science, and Department of Food and Nutrition, College of Human Ecology, Seoul National University; Laboratory of Molecular Oncology, Korea Institute of Radiological & Medical Sciences, Seoul; Department of Food Science & Technology, Chungnam National University, Taejeon, Korea; Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, Georgia; and Laboratory of Cancer Prevention, National Cancer Institute, Frederick, Maryland

Correspondence and requests for reprints should be addressed to Myung-Haing Cho, Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, 56-1, Sillim-dong, Seoul 151–742, Korea. E-mail: mchotox{at}snu.ac.kr

Inorganic phosphate (Pi) plays a critical role in diverse cellular functions. Among three classes of sodium/phosphate co-transporters (NPTs), two types have been identified in mammalian lung. The potential importance of Pi as a novel signaling molecule and pulmonary expression of NPTs with poor prognosis of diverse lung diseases including cancer have prompted us to begin to define the pathways by which Pi regulates nontumorigenic human bronchial epithelial cells. Pi activates Akt phosphorylation on Thr308 specifically, and activated signal transmits on the Raf/MEK/ERK signaling. Here, we report that Pi controls cell growth by activating ERK cascades and by facilitating the translocation of Mnk1 from cytosol into nucleus through an Akt-mediated MEK pathway. Sequentially, translocated Mnk1 increases eIF4E-BP1 phosphorylation. As a result, Pi stimulates cap-dependent protein translation. Such Akt-mediated signaling of inorganic phosphate may provide critical clues for treatment as well as prevention of diverse lung diseases.

Key Words: Akt • inorganic phosphate • Mnk1 • nontumorigenic human bronchial epithelial cells

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