CNKR3_HUMAN
ID CNKR3_HUMAN Reviewed; 555 AA.
AC Q6P9H4; C9IZX4; Q5SGD5; Q96N65;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Connector enhancer of kinase suppressor of ras 3;
DE Short=Connector enhancer of KSR 3;
DE AltName: Full=CNK homolog protein 3;
DE Short=CNK3;
DE AltName: Full=CNKSR family member 3;
DE AltName: Full=Maguin-like protein;
GN Name=CNKSR3; Synonyms=MAGI1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Tzolovsky G.I., McGurk L., Pathirana S., Slee R., Hillier S., Clinton M.,
RA Bownes M.;
RT "Cloning, expression and comparison of human, rat and mouse ML (maguin-
RT like) genes, and expression in mouse oogenesis.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [7]
RP INDUCTION BY ALDOSTERONE.
RX PubMed=19567370; DOI=10.1096/fj.09-134759;
RA Ziera T., Irlbacher H., Fromm A., Latouche C., Krug S.M., Fromm M.,
RA Jaisser F., Borden S.A.;
RT "Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key
RT role in the regulation of the epithelial sodium channel.";
RL FASEB J. 23:3936-3946(2009).
RN [8]
RP ALTERNATIVE SPLICING.
RX PubMed=22085542; DOI=10.1016/j.yexcr.2011.10.018;
RA Attar M.A., Salem J.C., Pursel H.S., Santy L.C.;
RT "CNK3 and IPCEF1 produce a single protein that is required for HGF
RT dependent Arf6 activation and migration.";
RL Exp. Cell Res. 318:228-237(2012).
RN [9]
RP FUNCTION, INTERACTION WITH ENAC; NEDDL4; RAF1 AND SGK1, SUBCELLULAR
RP LOCATION, AND DOMAIN.
RX PubMed=22851176; DOI=10.1074/jbc.m112.389148;
RA Soundararajan R., Ziera T., Koo E., Ling K., Wang J., Borden S.A.,
RA Pearce D.;
RT "Scaffold protein connector enhancer of kinase suppressor of Ras isoform 3
RT (CNK3) coordinates assembly of a multiprotein epithelial sodium channel
RT (ENaC)-regulatory complex.";
RL J. Biol. Chem. 287:33014-33025(2012).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-383, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
CC -!- FUNCTION: Involved in transepithelial sodium transport. Regulates
CC aldosterone-induced and epithelial sodium channel (ENaC)-mediated
CC sodium transport through regulation of ENaC cell surface expression.
CC Acts as a scaffold protein coordinating the assembly of an ENaC-
CC regulatory complex (ERC). {ECO:0000269|PubMed:22851176}.
CC -!- SUBUNIT: Interacts with epithelial sodium channel ENaC. Interacts
CC directly with SCNN1A (ENaC subunit alpha) and SCNN1B (ENaC subunit
CC beta) C-terminal tails. Interacts with ENaC regulatory proteins NEDD4L,
CC RAF1 and SGK1. {ECO:0000269|PubMed:22851176}.
CC -!- INTERACTION:
CC Q6P9H4; P42772: CDKN2B; NbExp=3; IntAct=EBI-10253274, EBI-711280;
CC Q6P9H4; P26196: DDX6; NbExp=3; IntAct=EBI-10253274, EBI-351257;
CC Q6P9H4; P38919: EIF4A3; NbExp=3; IntAct=EBI-10253274, EBI-299104;
CC Q6P9H4; Q5HYJ3-3: FAM76B; NbExp=3; IntAct=EBI-10253274, EBI-11956087;
CC Q6P9H4; Q92917: GPKOW; NbExp=3; IntAct=EBI-10253274, EBI-746309;
CC Q6P9H4; O75564-2: JRK; NbExp=3; IntAct=EBI-10253274, EBI-17181882;
CC Q6P9H4; O15049: N4BP3; NbExp=3; IntAct=EBI-10253274, EBI-2512055;
CC Q6P9H4; Q13287: NMI; NbExp=6; IntAct=EBI-10253274, EBI-372942;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22851176}. Apical
CC cell membrane {ECO:0000269|PubMed:22851176}; Peripheral membrane
CC protein {ECO:0000269|PubMed:22851176}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=CNK3;
CC IsoId=Q6P9H4-1; Sequence=Displayed;
CC Name=CNK3-IPCEF1-1; Synonyms=CNK3/IPCEF1 Long-1;
CC IsoId=G9CGD6-1; Sequence=External;
CC Name=CNK3-IPCEF1-2; Synonyms=CNK3/IPCEF1 Long-2;
CC IsoId=G9CGD6-2; Sequence=External;
CC Name=CNK3-IPCEF1-3; Synonyms=CNK3/IPCEF1 Short;
CC IsoId=G9CGD6-3; Sequence=External;
CC -!- INDUCTION: Up-regulated by aldosterone (at protein level).
CC {ECO:0000269|PubMed:19567370}.
CC -!- DOMAIN: The PDZ domain is required for interaction with ENaC and SGK1,
CC but not for interaction with NEDDL4 and RAF1.
CC {ECO:0000269|PubMed:22851176}.
CC -!- SIMILARITY: Belongs to the CNKSR family. {ECO:0000305}.
CC -!- CAUTION: The gene name MAGI1, shown in this entry as a synonym, is an
CC obsolete human gene nomenclature committee-approved name. It should be
CC noted that MAGI1 currently is the official name for the unrelated
CC membrane-associated guanylate kinase, WW and PDZ domain-containing
CC protein 1. {ECO:0000305}.
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DR EMBL; AY328891; AAQ92306.1; -; mRNA.
DR EMBL; AY328892; AAQ92307.1; -; mRNA.
DR EMBL; AY328893; AAQ92308.1; -; mRNA.
DR EMBL; AK055911; BAB71044.1; -; mRNA.
DR EMBL; AL357075; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL033376; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL590401; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW47699.1; -; Genomic_DNA.
DR EMBL; BC060761; AAH60761.1; -; mRNA.
DR CCDS; CCDS5246.1; -. [Q6P9H4-1]
DR RefSeq; NP_775786.2; NM_173515.3. [Q6P9H4-1]
DR AlphaFoldDB; Q6P9H4; -.
DR SMR; Q6P9H4; -.
DR BioGRID; 127531; 37.
DR IntAct; Q6P9H4; 19.
DR MINT; Q6P9H4; -.
DR STRING; 9606.ENSP00000475915; -.
DR iPTMnet; Q6P9H4; -.
DR PhosphoSitePlus; Q6P9H4; -.
DR BioMuta; CNKSR3; -.
DR DMDM; 74758311; -.
DR EPD; Q6P9H4; -.
DR jPOST; Q6P9H4; -.
DR MassIVE; Q6P9H4; -.
DR MaxQB; Q6P9H4; -.
DR PaxDb; Q6P9H4; -.
DR PeptideAtlas; Q6P9H4; -.
DR PRIDE; Q6P9H4; -.
DR ProteomicsDB; 67049; -.
DR ProteomicsDB; 7862; -.
DR Antibodypedia; 33402; 189 antibodies from 22 providers.
DR DNASU; 154043; -.
DR Ensembl; ENST00000607772.6; ENSP00000475915.1; ENSG00000153721.19. [Q6P9H4-1]
DR GeneID; 154043; -.
DR KEGG; hsa:154043; -.
DR MANE-Select; ENST00000607772.6; ENSP00000475915.1; NM_173515.4; NP_775786.2.
DR UCSC; uc003qpy.4; human. [Q6P9H4-1]
DR UCSC; uc063skq.1; human.
DR CTD; 154043; -.
DR DisGeNET; 154043; -.
DR GeneCards; CNKSR3; -.
DR HGNC; HGNC:23034; CNKSR3.
DR HPA; ENSG00000153721; Low tissue specificity.
DR MIM; 617476; gene.
DR neXtProt; NX_Q6P9H4; -.
DR OpenTargets; ENSG00000153721; -.
DR PharmGKB; PA134880153; -.
DR VEuPathDB; HostDB:ENSG00000153721; -.
DR eggNOG; KOG1738; Eukaryota.
DR GeneTree; ENSGT00940000154428; -.
DR HOGENOM; CLU_037920_0_0_1; -.
DR InParanoid; Q6P9H4; -.
DR OMA; PNSFLDH; -.
DR OrthoDB; 1121556at2759; -.
DR PhylomeDB; Q6P9H4; -.
DR TreeFam; TF326495; -.
DR PathwayCommons; Q6P9H4; -.
DR SignaLink; Q6P9H4; -.
DR BioGRID-ORCS; 154043; 9 hits in 1079 CRISPR screens.
DR ChiTaRS; CNKSR3; human.
DR GenomeRNAi; 154043; -.
DR Pharos; Q6P9H4; Tbio.
DR PRO; PR:Q6P9H4; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q6P9H4; protein.
DR Bgee; ENSG00000153721; Expressed in esophagus squamous epithelium and 168 other tissues.
DR ExpressionAtlas; Q6P9H4; baseline and differential.
DR Genevisible; Q6P9H4; HS.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:2000651; P:positive regulation of sodium ion transmembrane transporter activity; IEA:Ensembl.
DR GO; GO:0010765; P:positive regulation of sodium ion transport; ISS:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.30.42.10; -; 1.
DR InterPro; IPR010599; CNK2/3_dom.
DR InterPro; IPR017874; CRIC_domain.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed_sf.
DR Pfam; PF10534; CRIC_ras_sig; 1.
DR Pfam; PF06663; DUF1170; 1.
DR Pfam; PF00595; PDZ; 1.
DR Pfam; PF00536; SAM_1; 1.
DR SMART; SM00228; PDZ; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR PROSITE; PS51290; CRIC; 1.
DR PROSITE; PS50106; PDZ; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Cytoplasm; Membrane; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..555
FT /note="Connector enhancer of kinase suppressor of ras 3"
FT /id="PRO_0000311105"
FT DOMAIN 7..72
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 80..174
FT /note="CRIC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00621"
FT DOMAIN 211..293
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT DOMAIN 325..546
FT /note="DUF1170"
FT REGION 309..334
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 347..390
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 517..537
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 381
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BMA3"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CONFLICT 259
FT /note="I -> T (in Ref. 2; BAB71044)"
FT /evidence="ECO:0000305"
FT CONFLICT 334
FT /note="L -> P (in Ref. 1; AAQ92306/AAQ92307/AAQ92308)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 555 AA; 61904 MW; 456E284566D5EFC8 CRC64;
MEPVTKWSPK QVVDWTRGLD DCLQQYVHKF EREKINGEQL LQISHQDLEE LGVTRIGHQE
LVLEAVDLLC ALNYGLETDN MKNLVLKLRA SSHNLQNYIS SRRKSPAYDG NTSRKAPNEF
LTSVVELIGA AKALLAWLDR APFTGITDFS VTKNKIIQLC LDLTTTVQKD CFVAEMEDKV
LTVVKVLNGI CDKTIRSTTD PVMSQCACLE EVHLPNIKPG EGLGMYIKST YDGLHVITGT
TENSPADRSQ KIHAGDEVIQ VNQQTVVGWQ LKNLVKKLRE NPTGVVLLLK KRPTGSFNFT
PAPLKNLRWK PPLVQTSPPP ATTQSPESTM DTSLKKEKSA ILDLYIPPPP AVPYSPRDEN
GSFVYGGSSK CKQPLPGPKG SESPNSFLDQ ESRRRRFTIA DSDQLPGYSV ETNILPTKMR
EKTPSYGKPR PLSMPADGNW MGIVDPFARP RGHGRKGEDA LCRYFSNERI PPIIEESSSP
PYRFSRPTTE RHLVRGADYI RGSRCYINSD LHSSATIPFQ EEGTKKKSGS SATKSSSTEP
SLLVSWFTRL KLLTH
