Fig. 5.

Possible signal transduction pathway triggered by extracellular Pi in mammalian cells. Type III Na/Pi cotransporter, especially PiT-1, plays a major role in the sensing of the cells to the altered extracellular Pi concentration. Increased extracellular Pi binds to type III Na/Pi cotransporter on the plasma membrane, then induces activation of FGFR, Raf/MEK/ERK pathway, and Akt pathway, which subsequently regulates gene transcription through binding of several transcription factors (e.g., AP1, Nrf2, Egr1) to the phosphate response element in the nucleus. The signaling molecule(s) that link between type III Na/Pi cotransporter and FGFR are currently unknown.

Abbreviations: AP1, activator protein 1; Egr1, early growth response 1; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; FRS2α, fibroblast growth factor receptor substrate 2α; MEK, mitogen-activated protein kinase/ERK kinase; Nrf2, nuclear factor erythroid 2-related factor 2