The WNKs: atypical protein kinases with pleiotropic actions.
WNKs are serine/threonine kinases that comprise a unique branch of the kinome. They are so-named owing to the unusual placement of an essential catalytic lysine. WNKs have now been identified in diverse organisms. In humans and other mammals, four genes encode WNKs. WNKs are widely expressed at the message level, although data on protein expression is more limited. Soon after the WNKs were identified, mutations in genes encoding WNK1 and -4 were determined to cause the human disease familial hyperkalemic hypertension (also known as pseudohypoaldosteronism II, or Gordon's Syndrome). For this reason, a major focus of investigation has been to dissect the role of WNK kinases in renal regulation of ion transport. More recently, a different mutation in WNK1 was identified as the cause of hereditary sensory and autonomic neuropathy type II, an early-onset autosomal disease of peripheral sensory nerves. Thus the WNKs represent an important family of potential targets for the treatment of human disease, and further elucidation of their physiological actions outside of the kidney and brain is necessary. In this review, we describe the gene structure and mechanisms regulating expression and activity of the WNKs. Subsequently, we outline substrates and targets of WNKs as well as effects of WNKs on cellular physiology, both in the kidney and elsewhere. Next, consequences of these effects on integrated physiological function are outlined. Finally, we discuss the known and putative pathophysiological relevance of the WNKs.
Division of Nephrology and Hypertension, Oregon Health and Science University and Veterans Affairs Medical Center, Portland, Oregon 97239, USA. mccormij@ohsu.edu
James A
JA
McCormick
David H
DH
Ellison
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation; D058685:Genetic Pleiotropy; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000201:enzymology; D006801:Humans; D006973:Hypertension / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D005810:Multigene Family; D009369:Neoplasms / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000201:enzymology; D000076204:WNK Lysine-Deficient Protein Kinase 1
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human
Front Biosci. 2008 May 01;13:4938-52
18508559
J Am Soc Nephrol. 2003 Oct;14(10):2447-56
14514722
Cancer Res. 2005 Sep 1;65(17):7591-5
16140923
Pflugers Arch. 2004 Feb;447(5):710-21
12759755
J Cell Biochem. 2007 Oct 15;102(3):593-608
17729308
Am J Physiol Renal Physiol. 2008 Oct;295(4):F1199-206
18701621
Am J Hum Genet. 2004 May;74(5):1064-73
15060842
Curr Opin Investig Drugs. 2009 Jul;10(7):655-63
19579171
Biochem J. 2004 Feb 15;378(Pt 1):257-68
14611643
J Clin Invest. 2009 Nov;119(11):3278-89
19841541
Am J Hypertens. 2004 May;17(5 Pt 1):446-9
15110905
Curr Neurol Neurosci Rep. 2009 May;9(3):231-40
19348712
J Clin Invest. 2007 Nov;117(11):3403-11
17975670
Nature. 2007 Mar 8;446(7132):153-8
17344846
Science. 2002 Dec 6;298(5600):1912-34
12471243
EMBO Rep. 2008 Jan;9(1):70-5
18049475
J Neurosci. 2000 Feb 1;20(3):986-91
10648703
Am J Physiol Renal Physiol. 2008 Nov;295(5):F1472-84
18768590
J Biol Chem. 2000 Feb 11;275(6):4311-22
10660600
Gene. 2005 Jan 3;344:233-9
15656989
Am J Pathol. 2006 Jul;169(1):105-18
16816365
J Clin Endocrinol Metab. 2004 Aug;89(8):4025-30
15292344
J Biol Chem. 2009 Feb 6;284(6):3453-60
19068477
Biochem J. 1999 Nov 15;344 Pt 1:189-97
10548550
Am J Physiol Renal Physiol. 2006 Aug;291(2):F503-8
16554416
J Bone Miner Res. 2008 May;23(5):644-54
18433299
Kidney Int. 1998 Aug;54(2):464-72
9690213
J Neurochem. 2006 Nov;99(4):1114-21
17018027
Oncogene. 2001 Sep 6;20(39):5562-9
11571656
Pharmacol Ther. 2009 Sep;123(3):371-85
19501617
Nat Rev Neurosci. 2005 Mar;6(3):230-40
15738958
J Biol Chem. 2009 Jul 3;284(27):18471-80
19401467
J Physiol. 1996 Jan 1;490 ( Pt 1):215-28
8745289
Nucleic Acids Res. 2002 Sep 1;30(17):3754-66
12202761
Genomics. 1995 Jan 1;25(1):199-206
7774919
Cancer Res. 1996 May 15;56(10):2400-4
8625318
Cell. 1994 Nov 18;79(4):717-27
7954835
Oncogene. 2005 Aug 29;24(37):5742-50
16123807
Am J Physiol Renal Physiol. 2002 Oct;283(4):F826-38
12217875
Biochem Biophys Res Commun. 2010 Mar 19;393(4):844-8
20175999
Science. 2001 Jun 1;292(5522):1728-31
11387480
Am J Clin Pathol. 2003 Dec;120 Suppl:S3-13
15298139
J Histochem Cytochem. 2001 Aug;49(8):973-82
11457925
Cell. 1994 Sep 23;78(6):1073-87
7923357
Biosci Biotechnol Biochem. 2002 Nov;66(11):2429-36
12506983
J Membr Biol. 2004 Oct 1;201(3):109-37
15711773
Biochem Biophys Res Commun. 2006 Oct 20;349(2):804-8
16949040
Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17434-9
15583131
Mol Cell. 2004 Sep 10;15(5):741-51
15350218
J Clin Invest. 2003 Dec;112(12):1906-14
14679186
Am J Physiol. 1999 Mar;276(3):F367-81
10070160
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13327-32
8917590
Gene. 2004 Jun 23;335:109-19
15194194
Kidney Int. 1981 May;19(5):716-27
7026872
Am J Physiol. 1996 Jan;270(1 Pt 2):F211-9
8769842
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8558-63
16709664
Sci STKE. 2004 May 25;2004(235):pe24
15173600
Adv Exp Med Biol. 2004;559:379-85
18727257
Am J Physiol Renal Physiol. 2004 Jul;287(1):F17-24
15026302
J Biol Chem. 2000 Jun 2;275(22):16795-801
10828064
J Biol Chem. 2002 Dec 13;277(50):48456-62
12374799
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14034-9
19666518
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10741-6
8855250
Kidney Int. 2007 Jun;71(12):1322-4; author reply 1324-5
17554353
Plant Cell Physiol. 2002 Jun;43(6):675-83
12091722
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14109-14
14610273
Science. 2005 May 6;308(5723):826-33
15817814
Kidney Int. 1996 Jul;50(1):174-83
8807586
Pediatr Nephrol. 2006 Sep;21(9):1231-6
16683163
Physiol Rev. 2005 Apr;85(2):423-93
15788703
J Biol Chem. 2003 Dec 26;278(52):52848-56
14563843
FEBS J. 2008 Apr;275(8):1631-42
18312414
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16777-82
16275913
J Am Soc Nephrol. 2006 Jul;17(7):1867-74
16775035
Genes Dev. 2001 Sep 1;15(17):2203-8
11544177
Neuro Oncol. 2009 Aug;11(4):414-22
19001526
FEBS Lett. 2006 Feb 6;580(3):932-9
16427632
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4384-9
19240212
Nat Genet. 2002 Nov;32(3):384-92
12368912
Biochimie. 2003 Mar-Apr;85(3-4):455-63
12770784
Hypertension. 2003 Jun;41(6):1191-5
12719438
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4690-4
15070779
Immunol Rev. 2007 Jun;217:292-303
17498067
Physiol Rev. 2001 Apr;81(2):807-69
11274345
EMBO J. 1996 May 15;15(10):2381-7
8665845
Nat Neurosci. 2004 Mar;7(3):221-8
14966521
Am J Physiol Cell Physiol. 2005 Aug;289(2):C493-505
15800055
Am J Med. 2003 Apr 15;114(6):495-8
12727582
Ann N Y Acad Sci. 2008 Nov;1143:123-50
19076348
Orphanet J Rare Dis. 2008 Jul 30;3:22
18667063
Physiol Rev. 2000 Jan;80(1):277-313
10617770
J Biol Chem. 2006 Sep 29;281(39):28755-63
16887815
Science. 2006 Oct 13;314(5797):268-74
16959974
Can J Physiol Pharmacol. 2000 Aug;78(8):587-94
10958158
Oncogene. 2006 Jul 13;25(30):4172-82
16501604
Sci Signal. 2008 Nov 18;1(46):pe48
19018011
J Hypertens. 2010 Mar;28(3):465-77
20032787
J Physiol. 2006 Mar 1;571(Pt 2):275-86
16357011
Science. 2001 Aug 10;293(5532):1107-12
11498583
Mol Neurobiol. 2005 Oct;32(2):105-11
16215275
Cancer. 2005 Oct 1;104(7):1468-77
16088966
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1615-20
16428287
Biochem J. 2005 Oct 1;391(Pt 1):17-24
16083423
EMBO J. 2000 Jul 17;19(14):3565-75
10899111
Mol Cell Biol. 2000 Jan;20(1):379-88
10594040
Hum Mol Genet. 1997 Nov;6(12):2077-85
9328471
J Biol Chem. 2007 Apr 20;282(16):12097-103
17264080
Am J Physiol Renal Physiol. 2008 Aug;295(2):F438-45
18550644
Cell. 2000 Oct 27;103(3):525-35
11081638
Biochem J. 2008 Jan 15;409(2):321-31
18092945
Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10315-20
16006511
J Am Soc Nephrol. 2010 Jan;21(1):82-92
19875813
Mol Biol Cell. 2004 Sep;15(9):4278-88
15240817
Mol Psychiatry. 2004 Jul;9(7):646-63
15037868
Eur J Cancer. 2000 Jun;36(10):1269-74
10882865
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13698-703
14581612
J Clin Invest. 2009 Sep;119(9):2601-12
19690383
J Hum Genet. 2004;49(9):507-515
15309683
Int J Biochem Cell Biol. 2009 Apr;41(4):872-8
18793746
Int J Oncol. 2009 Jun;34(6):1513-20
19424568
Mol Cell Biol. 2003 Dec;23(24):9208-21
14645531
Am J Physiol. 1985 May;248(5 Pt 2):F638-49
3993787
Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10974-9
17578925
Circulation. 2005 Nov 29;112(22):3423-9
16301342
Cell. 2009 Aug 7;138(3):525-36
19665974
Am J Pathol. 2009 Sep;175(3):1315-27
19644017
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9727-32
10449762
J Physiol Sci. 2009 Mar;59(2):81-6
19340547
Hum Mol Genet. 2005 Jul 1;14(13):1805-14
15888480
Am J Physiol Renal Physiol. 2006 Dec;291(6):F1369-76
16788137
Kidney Int. 2008 Dec;74(11):1403-9
18800028
Hypertension. 2008 Dec;52(6):1149-54
18955660
Am J Physiol Renal Physiol. 2004 Oct;287(4):F593-601
15345493
J Physiol. 2007 Oct 1;584(Pt 1):333-45
17673510
Nat Genet. 2006 Oct;38(10):1124-32
16964266
J Biol Chem. 2007 Nov 9;282(45):32613-22
17848561
Plant Biol (Stuttg). 2008 Sep;10(5):548-62
18761494
Arch Biochem Biophys. 2008 Aug 1;476(1):33-42
18406336
Oncogene. 2007 Sep 6;26(41):6071-81
17667937
Clin Genet. 2007 Jul;72(1):19-22
17594395
Cell Signal. 2007 Aug;19(8):1621-32
17553668
J Clin Invest. 2007 Apr;117(4):1078-87
17380208
Ann Neurol. 2004 Oct;56(4):572-5
15455397
J Neuropathol Exp Neurol. 2004 Apr;63(4):314-22
15099021
Am J Physiol Renal Physiol. 2007 Feb;292(2):F545-54
17018846
Hypertension. 2005 Aug;46(2):295-300
15998707
Hypertension. 2008 Nov;52(5):974-9
18809789
Am J Physiol Renal Physiol. 2009 Sep;297(3):F704-12
19570885
Osteoporos Int. 2010 May;21(5):805-14
19876583
J Clin Oncol. 2000 Feb;18(3):636-45
10653879
Clin Genet. 2003 Nov;64(5):433-8
14616768
J Am Soc Nephrol. 2001 Jul;12(7):1335-1341
11423562
PLoS One. 2009;4(4):e5003
19347040
Oncogene. 2002 Mar 28;21(14):2236-44
11948406
Mol Cell Biol. 2002 Sep;22(17):6023-33
12167697
J Clin Invest. 2003 Apr;111(7):1039-45
12671053
Am J Physiol Renal Physiol. 2007 Apr;292(4):F1197-207
17182532
J Biol Chem. 2009 Jun 5;284(23):15717-28
19363035
J Clin Invest. 2008 Jul;118(7):2496-505
18521183
Blood. 2009 Feb 26;113(9):1875-91
18812465
Mol Cell Biol. 2000 Nov;20(21):8103-11
11027280
Chembiochem. 2004 Feb 6;5(2):170-6
14760737
J Clin Invest. 1989 Jan;83(1):113-26
2910903
Am J Physiol Cell Physiol. 2003 Jul;285(1):C96-101
12777254
J Am Soc Nephrol. 2009 Jun;20(6):1314-22
19470686
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):15061-6
19706464
Am J Kidney Dis. 2006 Oct;48(4):674-93
16997066
Med Oncol. 2010 Sep;27(3):833-42
19763917
J Med Genet. 2005 Oct;42(10):780-6
16199551
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2064-9
14769928
J Gen Physiol. 2005 Feb;125(2):113-25
15684092
Biochem Biophys Res Commun. 2008 Oct 17;375(2):225-9
18703016
J Biol Chem. 2002 Jan 4;277(1):5-8
11696533
Cancer Res. 1996 Dec 1;56(23):5309-18
8968075
Hypertension. 1999 Jul;34(1):4-7
10406815
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1976-81
16446421
J Biol Chem. 1996 Dec 13;271(50):31787-90
8943216
Nat Genet. 2003 Dec;35(4):372-6
14608358
Cell Metab. 2007 May;5(5):331-44
17488636
J Am Soc Nephrol. 1997 Dec;8(12):1823-30
9402083
Cancer Res. 2001 Mar 1;61(5):2038-46
11280764
Curr Opin Nephrol Hypertens. 2007 Sep;16(5):484-90
17693766
Biochemistry. 2009 Nov 3;48(43):10255-66
19739668
Curr Opin Cell Biol. 1998 Apr;10(2):262-7
9561851
Nat Genet. 2005 Jun;37(6):590-2
15908952
Kidney Int. 2006 Jun;69(12):2162-70
16688122
Am J Physiol Renal Physiol. 2006 Mar;290(3):F619-24
16204408
Kidney Int. 2000 Mar;57(3):809-15
10720933
Mol Cell Neurosci. 2003 Dec;24(4):1116-30
14697673
J Biol Chem. 2005 Oct 7;280(40):34218-23
16081417
Biochem Soc Trans. 2004 Nov;32(Pt 5):817-21
15494023
Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8458-63
18550832
J Cell Sci. 2008 Mar 1;121(Pt 5):675-84
18270262
J Am Soc Nephrol. 1998 Aug;9(8):1347-58
9697656
FEBS Lett. 2007 Aug 7;581(20):3887-91
17651736
Diabetes. 2005 Mar;54(3):638-47
15734838
Am J Physiol. 1995 Dec;269(6 Pt 2):F900-10
8594886
J Mol Endocrinol. 2008 Jan;40(1):3-12
18096992
J Clin Invest. 2005 May;115(5):1379-87
15841204
Med J Aust. 1964 Aug 22;2:305-6
14194482
Cell Signal. 2006 Jun;18(6):753-60
16376520
Physiol Rev. 2005 Apr;85(2):679-715
15788708
Nature. 1999 Apr 22;398(6729):728-31
10227297
J Endocrinol Invest. 2009 Nov;32(10):832-6
19605975
Cell Res. 2009 Jan;19(1):128-39
19114990
Am J Physiol Renal Physiol. 2007 Sep;293(3):F662-9
17507603
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9425-30
11459928
Science. 2004 Feb 6;303(5659):832-5
14764878
Biochem J. 2002 Aug 15;366(Pt 1):1-13
12047220
Pflugers Arch. 2005 Oct;451(1):160-7
15952037
J Am Coll Nutr. 1982;1(2):139-48
6764472
Physiol Rev. 2000 Jan;80(1):211-76
10617769
Am J Physiol Renal Physiol. 2001 Dec;281(6):F1021-7
11704552
J Clin Invest. 1995 Nov;96(5):2510-4
7593642
J Clin Invest. 1988 Aug;82(2):721-30
2841360
J Biol Chem. 2005 Jun 3;280(22):21622-8
15799971
J Neurosci. 2009 Feb 18;29(7):2162-6
19228968
Best Pract Res Clin Haematol. 2008 Dec;21(4):659-66
19041605
Br J Cancer. 1997;75(9):1256-62
9155043
Curr Opin Oncol. 2008 Nov;20(6):605-13
18841041
Endocrinology. 2009 May;150(5):2202-10
19106216
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10231-3
12149519
FASEB J. 2000 Feb;14(2):231-41
10657980
Biochem Biophys Res Commun. 2007 Feb 16;353(3):535-40
17194447
Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1279-86
18713958
Am J Physiol Cell Physiol. 2007 May;292(5):C1809-15
17267545
Nephron Physiol. 2004;96(3):p65-78
15056980
J Biol Chem. 2005 Dec 30;280(52):42685-93
16263722
J Biol Chem. 2004 Feb 27;279(9):7826-31
14681216
Science. 2003 Dec 5;302(5651):1727-36
14605208
Structure. 2004 Jul;12(7):1303-11
15242606
J Hum Genet. 2009 Aug;54(8):474-8
19609280
FEBS Lett. 1994 May 16;344(2-3):105-8
8187867
J Neurosci. 2002 Dec 1;22(23):10368-76
12451136
J Clin Endocrinol Metab. 2002 Jul;87(7):3248-54
12107233
J Biol Chem. 2002 Apr 19;277(16):14246-54
11834742
Physiology (Bethesda). 2005 Apr;20:134-9
15772302
J Biol Chem. 2003 Jul 25;278(30):27347-53
12740379
Hypertension. 2005 Oct;46(4):758-65
16172412
Cell Tissue Res. 2005 Jun;320(3):447-53
15846517
Cell Signal. 2008 Oct;20(10):1762-8
18593598
Curr Opin Neurol. 2002 Oct;15(5):605-9
12352004
Ann N Y Acad Sci. 2007 Nov;1116:360-75
18083938
Biochem Biophys Res Commun. 2004 May 7;317(3):939-44
15081430
J Biol Chem. 2000 Nov 24;275(47):37078-85
10978323
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16783-8
16275911
Am J Physiol Renal Physiol. 2006 Jun;290(6):F1305-14
16403833
Am J Physiol. 1985 Mar;248(3 Pt 2):F374-81
3976898
Neuron. 2001 Jan;29(1):255-66
11182096
J Biol Chem. 2009 May 1;284(18):12198-206
19244242
J Biol Chem. 2001 Oct 19;276(42):38349-52
11533044
Arch Intern Med. 1978 Apr;138(4):607-10
637641
J Am Soc Nephrol. 2006 Sep;17(9):2402-13
16899520
Ann Neurol. 2005 Jun;57(6):855-65
15929038
Am J Physiol Cell Physiol. 2006 Jan;290(1):C134-42
15930150
Biochim Biophys Acta. 1979 Dec 19;560(4):487-508
229906
Scott Med J. 1986 Jan;31(1):43-4
3961473
J Cell Biol. 2007 Jan 1;176(1):89-100
17190791
J Biol Chem. 2005 Jul 22;280(29):26653-8
15883153
J Biol Chem. 1998 Dec 4;273(49):32708-14
9830013
Hum Mol Genet. 2009 Oct 15;18(20):3978-86
19633012
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4020-4
17360470
J Biol Chem. 2007 Jul 27;282(30):21786-97
17548353
Clin Genet. 2008 Aug;74(2):134-44
18498374
Am J Pathol. 2002 Jul;161(1):313-9
12107116
Hypertension. 2004 Apr;43(4):766-8
14967840
Biochem Biophys Res Commun. 2008 Oct 31;375(4):651-4
18755144
Curr Pharm Des. 2009;15(15):1736-49
19442187
Hypertension. 2008 Nov;52(5):818-27
18852389
Steroids. 2008 Oct;73(9-10):979-84
18308353
J Biol Chem. 2009 Sep 18;284(38):25749-60
19632983
Physiol Genomics. 2001 Jan 19;4(3):165-74
11160995
Brain. 2009 Oct;132(Pt 10):2699-711
19651702
Am J Physiol Renal Physiol. 2009 Sep;297(3):F685-92
19587141
Am J Physiol Cell Physiol. 2009 Mar;296(3):C544-57
19144862
Nat Rev Nephrol. 2009 Aug;5(8):441-9
19546862
Arch Intern Med. 1978 Dec;138(12):1828-32
718348
Am J Physiol. 1994 Dec;267(6 Pt 1):C1607-15
7810602
N Engl J Med. 1991 Feb 14;324(7):472-6
1988833
Proc Natl Acad Sci U S A. 2007 May 22;104(21):8773-8
17517664
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):663-8
12522152
FASEB J. 2001 Mar;15(3):553-5
11259364
Am J Physiol. 1997 Jan;272(1 Pt 1):C173-83
9038823
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4
12515852
Arch Physiol Biochem. 2009 May;115(2):72-85
19485703
Biochem Biophys Res Commun. 2005 May 6;330(2):410-4
15796898
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10883-8
16832045
Biochemistry. 2006 Jan 10;45(1):213-23
16388597
Am J Physiol Renal Physiol. 2006 May;290(5):F1055-64
16303859
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4025-9
17360471
J Biol Chem. 2007 Jun 22;282(25):17985-17996
17392271
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14877-82
15465913