RAF1:SGK:TSC22D3:WPP ubiquitinates SCNN channels

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) comprises three subunits (alpha, beta and gamma) and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. The number of channels at the cell's surface (consequently its function) can be regulated. This is achieved by ubiquitination of SCNN via E3 ubiquitin-protein ligases (NED4L and WPP1) (Staub et al. 2000, Farr et al. 2000). NED4L/WPP1 is found in a signaling complex including Raf1 (RAF proto-oncogene serine/threonine-protein kinase), SGK (serum/glucocorticoid-regulated kinase) and GILZ (glucocorticoid-induced leucine zipper protein, TSC22D3) (Soundararajan et al. 2009). Ubiquitinated SCNN (Ub-SCNN) is targeted for degradation so a lesser number of channels are present at the cell surface, reducing the amount of Na+ absorption. Proline-rich sequences at the C-terminus of SCNNs include the PY motif containing a PPxY sequence. PY motifs bind WW domains of NED4L/WPP1. Protein kinases with no lysine K (WNKs) can activate SCNN activity by interacting non-enzymatically with the signaling complex, specifically SGK although the mechanism is unknown (Heise et al. 2010).
Literature References
PubMed ID Title Journal Year
20525693 Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members

Earnest, S, Cobb, MH, Deaton, SL, Cha, SK, Heise, CJ, Sengupta, S, Xu, Y, Stippec, S, Xu, BE, Zhao, Y, Juang, YC, Cheng, CJ, Huang, CL

J. Biol. Chem. 2010
17381423 Epithelial sodium channel (ENaC) is multi-ubiquitinated at the cell surface

Rohlfs, M, Wiemuth, D, Ke, Y, McDonald, FJ

Biochem J 2007
19380724 Epithelial sodium channel regulated by differential composition of a signaling complex

Melters, D, Wang, J, Soundararajan, R, Pearce, D, Shih, IC

Proc. Natl. Acad. Sci. U.S.A. 2009
10720933 Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination

Horisberger, JD, Ishikawa, T, Rotin, D, Kanelis, V, Plant, P, Schild, L, Saleki, R, Abriel, H, Staub, O

Kidney Int. 2000
10642508 Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits

Snyder, PM, Farr, TJ, Coddington-Lawson, SJ, McDonald, FJ

Biochem. J. 2000
Catalyst Activity

ubiquitin-protein transferase activity of RAF1:SGK:TSC22D3:WPP [cytosol]

This event is regulated
Positively by
Orthologous Events
Cite Us!