TY - JOUR
T1 - WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway
AU - Kim, Ji Hee
AU - Hwang, Kyu Hee
AU - Eom, Minseob
AU - Kim, Minseon
AU - Park, Eun Young
AU - Jeong, Yangsik
AU - Park, Kyu Sang
AU - Cha, Seung Kuy
N1 - Publisher Copyright:
© FASEB
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Deregulation of Ca2+ signaling has been regarded as one of the key features of cancer progression. Lysine-deficient protein kinase 1 (WNK1), a major regulator of renal ion transport, regulates Ca2+ signaling through stimulating the phosphatidylinositol 4-kinase IIIα (PI4KIIIα) to activate Gαq-coupled receptor/PLC-β signaling. However, the contribution of WNK1-mediated Ca2+ signaling in the development of clear-cell renal-cell carcinoma (ccRCC) is yet unknown. We found that the canonical transient receptor potential channel (TRPC)6 was widely expressed in ccRCC tissues and functioned as a primary Ca2+ influx mechanism. We further identified that the expressions of WNK1, PI4KIIIcα, TRPC6, and the nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were elevated in the tumor tissues compared with the adjacent normal tissues. WNK1 expression was directly associated with the nuclear grade of ccRCC tissues. Functional experiments showed that WNK1 activated TRPC6-mediated Ca2+ influx and current by stimulating PI4KIIIα. Notably, the inhibition of WNK1-mediated TRPC6 activation and its downstream substrate calcineurin attenuated NFATc1 activation and the subsequent migration and proliferation of ccRCC. These findings revealed a novel perspective of WNK1 signaling in targeting the TRPC6-NFATc1 pathway as a therapeutic potential for renal-cell carcinoma.—Kim, J.-H., Hwang, K.-H., Eom, M., Kim, M., Park, E. Y., Jeong, Y., Park, K.-S., Cha, S.-K. WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway. FASEB J. 33, 8588–8599 (2019). www.fasebj.org.
AB - Deregulation of Ca2+ signaling has been regarded as one of the key features of cancer progression. Lysine-deficient protein kinase 1 (WNK1), a major regulator of renal ion transport, regulates Ca2+ signaling through stimulating the phosphatidylinositol 4-kinase IIIα (PI4KIIIα) to activate Gαq-coupled receptor/PLC-β signaling. However, the contribution of WNK1-mediated Ca2+ signaling in the development of clear-cell renal-cell carcinoma (ccRCC) is yet unknown. We found that the canonical transient receptor potential channel (TRPC)6 was widely expressed in ccRCC tissues and functioned as a primary Ca2+ influx mechanism. We further identified that the expressions of WNK1, PI4KIIIcα, TRPC6, and the nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were elevated in the tumor tissues compared with the adjacent normal tissues. WNK1 expression was directly associated with the nuclear grade of ccRCC tissues. Functional experiments showed that WNK1 activated TRPC6-mediated Ca2+ influx and current by stimulating PI4KIIIα. Notably, the inhibition of WNK1-mediated TRPC6 activation and its downstream substrate calcineurin attenuated NFATc1 activation and the subsequent migration and proliferation of ccRCC. These findings revealed a novel perspective of WNK1 signaling in targeting the TRPC6-NFATc1 pathway as a therapeutic potential for renal-cell carcinoma.—Kim, J.-H., Hwang, K.-H., Eom, M., Kim, M., Park, E. Y., Jeong, Y., Park, K.-S., Cha, S.-K. WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway. FASEB J. 33, 8588–8599 (2019). www.fasebj.org.
KW - calcieurin
KW - calcium signaling
KW - phosphatidylinositol-4,5-bishosphate
KW - renal-cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85069235424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069235424&partnerID=8YFLogxK
U2 - 10.1096/fj.201802019RR
DO - 10.1096/fj.201802019RR
M3 - Article
C2 - 31022353
AN - SCOPUS:85069235424
SN - 0892-6638
VL - 33
SP - 8588
EP - 8599
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -
