Journal
CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 47, Issue 4, Pages 349-359Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/10409238.2012.678285
Keywords
Aldosterone signaling; ENaC-regulatory complex; scaffold protein; PDZ domains; lipid rafts; mTOR; PI3K; GILZ1; SGK1; Nedd4-2
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Funding
- National Institutes of Health [K01-DK078679, R01-DK56695, R01-DK85101]
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The control of fluid and electrolyte homeostasis in vertebrates requires the integration of a diverse set of signaling inputs, which control epithelial Na+ transport, the principal ionic component of extracellular fluid. The key site of regulation is a segment of the kidney tubules, frequently termed the aldosterone-sensitive distal nephron, wherein the epithelial Na+ channel (or ENaC) mediates apical ion entry. Na+ transport in this segment is strongly regulated by the salt-retaining hormone, aldosterone, which acts through the mineralocorticoid receptor (MR) to influence the expression of a selected set of target genes, most notably the serine-threonine kinase SGK1, which phosphorylates and inhibits the E3 ubiquitin ligase Nedd4-2. It has long been known that ENaC activity is tightly regulated in vertebrate epithelia. Recent evidence suggests that SGK1 and Nedd4-2, along with other ENaC-regulatory proteins, physically associate with each other and with ENaC in a multi-protein complex. The various components of the complex are regulated by diverse signaling networks, including steroid receptor-,PI3-kinase-, mTOR-, and Raf-MEK-ERK-dependent pathways. In this review, we focus on the organization of the targets of these pathways by multidomain scaffold proteins and lipid platforms into a unified complex, thereby providing a molecular basis for signal integration in the control of ENaC.
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