Transactivation of the IGF-1R by aldosterone.
Activation of epithelial sodium channels (ENaC) by aldosterone, insulin, or insulin-like growth factor-1 (IGF-1) in renal epithelial cells (including the Xenopus laevis renal cell line A6) appears to share some common signaling elements subsequent to the initial insulin or IGF-1 receptor activation. Previously, the convergence point for insulin or IGF-1 and aldosterone signaling was assumed to be downstream of the receptor at the level of phosphatidylinositol 3-kinase (PI3-K); however, this study shows aldosterone directly transactivates the IGF-1 receptor (IGF-1R). In A6 cells, 10-min exposure to aldosterone increased the phosphorylation of the IGF-1 receptor, insulin receptor substrate-1 (IRS-1), and Akt (PKB). Furthermore, aldosterone activated PI3-K and phosphorylation of the most downstream element, Akt, was blocked by the specific PI3-K inhibitor LY-294002. Transactivation requires aldosterone binding to the mineralocorticoid/glucocorticoid receptor and does not require transcription.
Holzman
Jennifer L
JL
Emory Univ. School of Medicine, Dept. of Medicine, Renal Div., 1639 Pierce Dr., Rm. 3327, Atlanta, GA 30322, USA. jennifer.holzman@emory.edu
Liu
Lian
L
Duke
Billie Jeanne
BJ
Kemendy
Alexandra E
AE
Eaton
Douglas C
DC
D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D015735:Mifepristone / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects*; D029867:Xenopus Proteins; D014982:Xenopus laevis
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D029867:Xenopus Proteins; C526294:irs1 protein, Xenopus; D003609:Dactinomycin; D013148:Spironolactone; D015735:Mifepristone; D000450:Aldosterone; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt