Epithelial sodium channel regulated by differential composition of a signaling complex.
Hormonal control of transepithelial sodium (Na(+)) transport utilizes phosphatidylinositide 3'-kinase (PI3K) and Raf-MAPK/ERK kinase (MEK)-ERK-dependent signaling pathways, which impact numerous cell functions. How signals transmitted by these pathways are sorted and appropriately transmitted to alter Na(+) transport without altering other physiologic processes is not well understood. Here, we report the identification of a signaling complex that selectively modulates the cell surface expression of the epithelial sodium channel (ENaC), an ion channel that is essential for fluid and electrolyte balance in mammals. Raf-1 and the ubiquitin ligase, Nedd4-2, are constitutively-expressed inhibitory components of this ENaC regulatory complex, which interact with, and decrease the expression of, cell surface ENaC. The activities of Nedd4-2 and Raf-1 are inhibited cooperatively by the PI3K-dependent kinase serum- and glucocorticoid-induced kinase 1 (SGK1), and the Raf-1-interacting protein glucocorticoid-induced leucine zipper (GILZ1), which are aldosterone-stimulated components of the complex. Together, SGK1 and GILZ1 synergistically stimulate ENaC cell surface expression. Interestingly, GILZ1 and SGK1 do not have synergistic, and in fact have opposite, effects on an unrelated activity, FKHRL1-driven gene transcription. Together, these data suggest that GILZ1 and SGK1 provide a physical and functional link between the PI3K- and Raf-1-dependent signaling modules and represent a unique mechanism for specifically controlling Na(+) transport without inappropriately activating other cell functions.
Soundararajan
Rama
R
Division of Nephrology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Melters
Daniël
D
Shih
I-Chia
IC
Wang
Jian
J
Pearce
David
D
D000818:Animals; D001665:Binding Sites; D019921:Biotinylation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008954:Models, Biological; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D007473:Ion Channels; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D012964:Sodium; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C404226:TSC22D3 protein, human; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human