Premium
EGFR augments cell proliferation in polycystic kidney disease through activation of a novel ion channel
Author(s) -
Zhang ZhiRen,
Chu WenFeng,
Song Binlin,
Gooz Monika,
Baldys Aleksander,
Kolb Robert J.,
Steele Stacy,
Houston Amber,
Haycraft Courtney J.,
Owsianik Grzegorz,
Nilius Bernd,
Raymond John R.,
Komlosi Peter,
Bell Phillip D.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.604.6
Subject(s) - cilium , microbiology and biotechnology , ion channel , chemistry , epidermal growth factor , patch clamp , tyrosine kinase , biology , signal transduction , receptor , biochemistry
Previously we have proposed that dysregulation of Ca 2+ 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 Ca 2+ channel and to determine if it is regulated by the epidermal growth factor receptor (EGFR). Using patch‐clamp, a 23‐pS Ca 2+ ‐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 Ca 2+ channel. Our results provide evidence that EGFR activates a TRPP2\TRPV4 channel complex that leads to Ca 2+ entry and contributes to hyper‐proliferation of orpk cilia (‐) cells.