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PMID:11244092

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Citation

Harvey, KF, Dinudom, A, Cook, DI and Kumar, S (2001) The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J. Biol. Chem. 276:8597-601

Abstract

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPxY, motif which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddle's syndrome, where mutations delete or alter the PPxY motif of either the beta or gamma subunits, has been proposed to result in increased ENaC activity. Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC. We demonstrate that KIAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na(+)-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC.

Links

PubMed Online version:10.1074/jbc.C000906200

Keywords

Animals; Calcium-Binding Proteins/physiology; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channel; Ligases/genetics; Ligases/physiology; Male; Mice; Protein Subunits; RNA, Messenger/analysis; Sodium/pharmacology; Sodium Channels/chemistry; Sodium Channels/physiology; Ubiquitin-Protein Ligases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SCNNA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96PU5

F

Seeded From UniProt

complete

HUMAN:SCNNB

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96PU5

F

Seeded From UniProt

complete

HUMAN:SCNNG

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96PU5

F

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P51170

F

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P51168

F

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P37088

F

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0030104: water homeostasis

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0016567: protein ubiquitination

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0007588: excretion

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0006883: cellular sodium ion homeostasis

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0006814: sodium ion transport

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0010038: response to metal ion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0017080: sodium channel regulator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NED4L

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0045807: positive regulation of endocytosis

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NED4L

involved_in

GO:0042176: regulation of protein catabolic process

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete


See also

References

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