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

• Published in: American journal of respiratory cell and molecular biology Vol. 35; no. 5; pp. 528 - 539
• Main Authors: Chang, Seung-Hee, Yu, Kyeong Nam, Lee, Yeon-Sook, An, Gil-Hwan, Beck, George R., Jr, Colburn, Nancy H, Lee, Kee-Ho, Cho, Myung-Haing
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01.11.2006; American Thoracic Society
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Fractionation; Cells, Cultured; Enzyme Activation; Enzyme Inhibitors - metabolism; Epithelial Cells - cytology; Epithelial Cells - metabolism; Foscarnet - metabolism; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Sequence Data; Phosphates - metabolism; Phosphoproteins - metabolism; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Respiratory Mucosa - cytology; RNA, Small Interfering - metabolism; Signal Transduction - physiology; Threonine - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2005-0477OC

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.