Egfr Augments Cell Proliferation In Polycystic Kidney Disease Through Activation Of A Novel Ion Channel

Previously we have proposed that dysregulation of Ca2+ entry mechanisms due to loss of cilia in collecting duct cells leads to enhanced cell proliferation and cystogenesis. These studies were performed to identify this Ca2+ channel and to determine if it is regulated by the epidermal growth factor receptor (EGFR). Using patch-clamp, a 23-pS Ca2+-permeable channel was found at the apical membrane of orpk cilia(+) and orpk cilia(-) collecting duct cells. This channel was markedly activated by EGF only from the apical surface in orpk cilia(-) cells; in orpk cilia(+) cells channel activity was elevated only by basolateral administration of EGF. EGFR was more abundant in orpk cilia(-) compared to cilia(+) cells and EGF-induced channel activity was ~3.5-fold higher in orpk cilia(-) cells compared to orpk cilia(+) cells. Effects of EGF on this channel were blunted by both AG1478 and PD98059; tyrosine kinase and MAP kinase inhibitors, respectively. Using shRNA, patch-clamp, and co-immunoprecipitation we identified the 23-pS channel as a multimer of TRP channels, TRPP2 and TRPV4. EGR enhanced cell proliferation in orpk cilia(-) cells, at least in part, through activation of the 23-pS Ca2+ channel. Our results provide evidence that EGFR activates a TRPP2\TRPV4 channel complex that leads to Ca2+ entry and contributes to hyper-proliferation of orpk cilia (-) cells.