Reactome | RAF1:SGK:TSC22D3:WPP ubiquitinates SCNN channels

RAF1:SGK:TSC22D3:WPP ubiquitinates SCNN channels

Stable Identifier

R-HSA-2682349

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

RAF1:SGK:TSC22D3:WPP ubiquitinates SCNN channels

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