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PMID:16275913

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Citation

Rinehart, J, Kahle, KT, de Los Heros, P, Vazquez, N, Meade, P, Wilson, FH, Hebert, SC, Gimenez, I, Gamba, G and Lifton, RP (2005) WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proc. Natl. Acad. Sci. U.S.A. 102:16777-82

Abstract

WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K(+) secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.

Links

PubMed PMC1283841 Online version:10.1073/pnas.0508303102

Keywords

Animals; Blood Pressure/physiology; COS Cells; Cercopithecus aethiops; Electrophoresis, Polyacrylamide Gel; Homeostasis; Kidney/physiology; Mice; Microscopy, Fluorescence; Phosphorylation; Protein-Serine-Threonine Kinases/physiology; Sodium-Potassium-Chloride Symporters/physiology; Symporters/physiology; Transfection

Significance

Annotations

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

MOUSE:ZO1

located_in

GO:0005923: bicellular tight junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:S12A1

involved_in

GO:0034220: ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:S12A1

involved_in

GO:0070294: renal sodium ion absorption

ECO:0000305: curator inference used in manual assertion

GO:0034220

P

Seeded From UniProt

complete

RAT:S12A3

involved_in

GO:0035725: sodium ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:S12A3

involved_in

GO:0070294: renal sodium ion absorption

ECO:0000305: curator inference used in manual assertion

GO:0035725

P

Seeded From UniProt

complete

RAT:S12A3

enables

GO:0015081: sodium ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:S12A3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WNK3

located_in

GO:0005912: adherens junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:WNK3

located_in

GO:0005923: bicellular tight junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:1903078: positive regulation of protein localization to plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:0046777: protein autophosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:0032414: positive regulation of ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:0010765: positive regulation of sodium ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNK3

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:2000651: positive regulation of sodium ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNK3

involved_in

GO:0010800: positive regulation of peptidyl-threonine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CADH1

part_of

GO:0005912: adherens junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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