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GILZ1: a key molecular determinant of intracellular signaling specificity governing epithelial sodium transport
Author(s) -
Soundararajan Rama,
Wang Jian,
Melters Daniel,
Shih IChia,
Pearce David
Publication year - 2010
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.24.1_supplement.701.9
Subject(s) - sgk1 , epithelial sodium channel , nedd4 , renal sodium reabsorption , aldosterone , ubiquitin ligase , microbiology and biotechnology , chemistry , leucine zipper , reabsorption , ubiquitin , kinase , biology , biochemistry , sodium , endocrinology , transcription factor , organic chemistry , gene
The kidney plays an important role in the long‐term regulation of sodium (Na + ) balance, which is central to the maintenance of appropriate extracellular fluid volume and blood pressure. Renal Na + reabsorption via the epithelial Na + channel (ENaC) is dependent on the mineralocorticoid aldosterone. Aldosterone‐mediated Na + transport includes the function of the PI3K‐dependent kinase SGK1, and a small leucine‐zipper protein called GILZ1, which negatively regulates the Raf‐MEK‐ERK1/2 MAPK pathway. Our studies suggest that GILZ1 and SGK1 demonstrate functional synergy in the modulation of epithelial Na + transport, and point to a key role for GILZ1 as a scaffolding protein capable of harnessing pleiotropic signaling pathways to control Na + transport. SGK1 is a short‐lived protein which is predominantly targeted to the ER to undergo rapid proteasome‐mediated degradation. GILZ1 redirects SGK1 away from the ER, and selectively recruits it to an ENaC‐regulatory complex (ERC), which includes Raf‐1 and the ubiquitin ligase Nedd4–2, the constitutively expressed inhibitory components of the ERC. Once in the ERC, GILZ1 and SGK1 (the aldosterone‐stimulated components of the ERC) synergistically stimulate ENaC surface expression and function by disinhibiting the inhibitory activities of Raf‐1 and Nedd4–2. This work is supported by NIH K01‐DK078679 (to RS) and R01‐DK51151 (to DP).