A phosphoinositide 3-kinase (PI3K)-serum- and glucocorticoid-inducible kinase 1 (SGK1) pathway promotes Kv7.1 channel surface expression by inhibiting Nedd4-2 protein

Andersen, Martin Nybo; Krzystanek, Katarzyna; Petersen, Frederic; Bomholtz, Sofia Hammami; Olesen, Søren-Peter; Abriel, Hugues; Jespersen, Thomas; Rasmussen, Hanne Borger (2013). A phosphoinositide 3-kinase (PI3K)-serum- and glucocorticoid-inducible kinase 1 (SGK1) pathway promotes Kv7.1 channel surface expression by inhibiting Nedd4-2 protein. Journal of biological chemistry, 288(52), pp. 36841-54. American Society for Biochemistry and Molecular Biology 10.1074/jbc.M113.525931

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Epithelial cell polarization involves several kinase signaling cascades that eventually divide the surface membrane into an apical and a basolateral part. One kinase, which is activated during the polarization process, is phosphoinositide 3-kinase (PI3K). In MDCK cells, the basolateral potassium channel Kv7.1 requires PI3K activity for surface-expression during the polarization process. Here, we demonstrate that Kv7.1 surface expression requires tonic PI3K activity as PI3K inhibition triggers endocytosis of these channels in polarized MDCK. Pharmacological inhibition of SGK1 gave similar results as PI3K inhibition, whereas overexpression of constitutively active SGK1 overruled it, suggesting that SGK1 is the primary downstream target of PI3K in this process. Furthermore, knockdown of the ubiquitin ligase Nedd4-2 overruled PI3K inhibition, whereas a Nedd4-2 interaction-deficient Kv7.1 mutant was resistant to both PI3K and SGK1 inhibition. Altogether, these data suggest that a PI3K-SGK1 pathway stabilizes Kv7.1 surface expression by inhibiting Nedd4-2-dependent endocytosis and thereby demonstrates that Nedd4-2 is a key regulator of Kv7.1 localization and turnover in epithelial cells.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
UniBE Contributor:	Abriel, Hugues
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Language:	English
Submitter:	Verena de Serra Frazao-Bill
Date Deposited:	28 Mar 2014 09:22
Last Modified:	05 Dec 2022 14:29
Publisher DOI:	10.1074/jbc.M113.525931
PubMed ID:	24214981
Uncontrolled Keywords:	E3, Ubiquitin Ligase Endocytosis, Ion Channels, KCNQ1, PI 3-Kinase (PI3K), Trafficking
URI:	https://boris.unibe.ch/id/eprint/43783