NKD2_HUMAN
ID NKD2_HUMAN Reviewed; 451 AA.
AC Q969F2; Q96EK8; Q9BSN0;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Protein naked cuticle homolog 2;
DE Short=Naked-2;
DE Short=hNkd2;
GN Name=NKD2;
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] (ISOFORM 1).
RX PubMed=11356022; DOI=10.1006/dbio.2001.0238;
RA Wharton K.A. Jr., Zimmermann G., Rousset R., Scott M.P.;
RT "Vertebrate proteins related to Drosophila Naked Cuticle bind Dishevelled
RT and antagonize Wnt signaling.";
RL Dev. Biol. 234:93-106(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC TISSUE=Fetus;
RX PubMed=11604995;
RA Katoh M.;
RT "Molecular cloning, gene structure, and expression analyses of NKD1 and
RT NKD2.";
RL Int. J. Oncol. 19:963-969(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 127-451 (ISOFORM 1).
RC TISSUE=Placenta, and Uterus;
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 [4]
RP FUNCTION, INTERACTION WITH TGFA, SUBCELLULAR LOCATION, MYRISTOYLATION AT
RP GLY-2, AND MUTAGENESIS OF GLY-2.
RX PubMed=15064403; DOI=10.1073/pnas.0401294101;
RA Li C., Franklin J.L., Graves-Deal R., Jerome W.G., Cao Z., Coffey R.J.;
RT "Myristoylated Naked2 escorts transforming growth factor alpha to the
RT basolateral plasma membrane of polarized epithelial cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:5571-5576(2004).
RN [5]
RP DOMAIN, STRUCTURE BY NMR, AND CIRCULAR DICHROISM.
RX PubMed=17045239; DOI=10.1016/j.bbrc.2006.09.121;
RA Hu T., Krezel A.M., Li C., Coffey R.J.;
RT "Structural studies of human Naked2: a biologically active intrinsically
RT unstructured protein.";
RL Biochem. Biophys. Res. Commun. 350:911-915(2006).
RN [6]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17553928; DOI=10.1091/mbc.e07-02-0172;
RA Li C., Hao M., Cao Z., Ding W., Graves-Deal R., Hu J., Piston D.W.,
RA Coffey R.J.;
RT "Naked2 acts as a cargo recognition and targeting protein to ensure proper
RT delivery and fusion of TGF-{alpha} containing exocytic vesicles at the
RT lower lateral membrane of polarized MDCK cells.";
RL Mol. Biol. Cell 18:3081-3093(2007).
RN [7]
RP UBIQUITINATION, AND INTERACTION WITH TGFA AND RNF25.
RX PubMed=18757723; DOI=10.1073/pnas.0806298105;
RA Ding W., Li C., Hu T., Graves-Deal R., Fotia A.B., Weissman A.M.,
RA Coffey R.J.;
RT "EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-
RT mediated ubiquitylation and proteasomal degradation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:13433-13438(2008).
CC -!- FUNCTION: Cell autonomous antagonist of the canonical Wnt signaling
CC pathway. May activate a second Wnt signaling pathway that controls
CC planar cell polarity (By similarity). Required for processing of TGFA
CC and for targeting of TGFA to the basolateral membrane of polarized
CC epithelial cells. {ECO:0000250, ECO:0000269|PubMed:15064403,
CC ECO:0000269|PubMed:17553928}.
CC -!- SUBUNIT: Interacts with DVL1, DVL2, DVL3 and PPP2R3A (By similarity).
CC Interacts with RNF25 and TGFA (via cytoplasmic domain). {ECO:0000250,
CC ECO:0000269|PubMed:15064403, ECO:0000269|PubMed:18757723}.
CC -!- INTERACTION:
CC Q969F2; Q96PM5: RCHY1; NbExp=2; IntAct=EBI-1538629, EBI-947779;
CC Q969F2; Q96BH1: RNF25; NbExp=2; IntAct=EBI-1538629, EBI-2129220;
CC Q969F2; P01135: TGFA; NbExp=3; IntAct=EBI-1538629, EBI-1034374;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15064403,
CC ECO:0000269|PubMed:17553928}. Cytoplasm {ECO:0000269|PubMed:15064403,
CC ECO:0000269|PubMed:17553928}. Cytoplasmic vesicle
CC {ECO:0000269|PubMed:15064403, ECO:0000269|PubMed:17553928}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q969F2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q969F2-2; Sequence=VSP_027900, VSP_027901;
CC -!- TISSUE SPECIFICITY: Expressed in kidney, lung, pancreas and spleen.
CC {ECO:0000269|PubMed:11604995}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal kidney and lung.
CC {ECO:0000269|PubMed:11604995}.
CC -!- DOMAIN: The N-terminal domain comprising the first 217 amino acid
CC residues is mostly unstructured. {ECO:0000269|PubMed:17045239}.
CC -!- PTM: Ubiquitinated, leading to rapid proteasomal degradation.
CC Interaction with TGFA interferes with RNF25 binding and protects
CC against ubiquitination mediated by RNF25.
CC {ECO:0000269|PubMed:18757723}.
CC -!- SIMILARITY: Belongs to the NKD family. {ECO:0000305}.
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DR EMBL; AF358137; AAK57486.1; -; mRNA.
DR EMBL; AB062887; BAB70501.1; -; mRNA.
DR EMBL; BC004940; AAH04940.1; -; mRNA.
DR EMBL; BC012176; AAH12176.1; -; mRNA.
DR CCDS; CCDS3859.1; -. [Q969F2-1]
DR CCDS; CCDS59486.1; -. [Q969F2-2]
DR RefSeq; NP_001258011.1; NM_001271082.1. [Q969F2-2]
DR RefSeq; NP_149111.1; NM_033120.3. [Q969F2-1]
DR AlphaFoldDB; Q969F2; -.
DR BioGRID; 124517; 34.
DR DIP; DIP-38642N; -.
DR IntAct; Q969F2; 23.
DR MINT; Q969F2; -.
DR STRING; 9606.ENSP00000296849; -.
DR iPTMnet; Q969F2; -.
DR PhosphoSitePlus; Q969F2; -.
DR BioMuta; NKD2; -.
DR DMDM; 74716653; -.
DR EPD; Q969F2; -.
DR jPOST; Q969F2; -.
DR MassIVE; Q969F2; -.
DR PaxDb; Q969F2; -.
DR PeptideAtlas; Q969F2; -.
DR PRIDE; Q969F2; -.
DR ProteomicsDB; 75748; -. [Q969F2-1]
DR ProteomicsDB; 75749; -. [Q969F2-2]
DR Antibodypedia; 22295; 155 antibodies from 29 providers.
DR DNASU; 85409; -.
DR Ensembl; ENST00000274150.4; ENSP00000274150.4; ENSG00000145506.14. [Q969F2-2]
DR Ensembl; ENST00000296849.10; ENSP00000296849.5; ENSG00000145506.14. [Q969F2-1]
DR Ensembl; ENST00000610777.2; ENSP00000482896.1; ENSG00000276920.4. [Q969F2-2]
DR Ensembl; ENST00000616539.4; ENSP00000479003.1; ENSG00000276920.4. [Q969F2-1]
DR GeneID; 85409; -.
DR KEGG; hsa:85409; -.
DR MANE-Select; ENST00000296849.10; ENSP00000296849.5; NM_033120.4; NP_149111.1.
DR UCSC; uc003jbt.3; human. [Q969F2-1]
DR CTD; 85409; -.
DR DisGeNET; 85409; -.
DR GeneCards; NKD2; -.
DR HGNC; HGNC:17046; NKD2.
DR HPA; ENSG00000145506; Tissue enhanced (lung).
DR MIM; 607852; gene.
DR neXtProt; NX_Q969F2; -.
DR OpenTargets; ENSG00000145506; -.
DR PharmGKB; PA31638; -.
DR VEuPathDB; HostDB:ENSG00000145506; -.
DR eggNOG; ENOG502QWMF; Eukaryota.
DR GeneTree; ENSGT00440000033589; -.
DR HOGENOM; CLU_035610_1_0_1; -.
DR InParanoid; Q969F2; -.
DR OMA; PMVQRHE; -.
DR OrthoDB; 986055at2759; -.
DR PhylomeDB; Q969F2; -.
DR TreeFam; TF328786; -.
DR PathwayCommons; Q969F2; -.
DR SignaLink; Q969F2; -.
DR BioGRID-ORCS; 85409; 15 hits in 1068 CRISPR screens.
DR GenomeRNAi; 85409; -.
DR Pharos; Q969F2; Tbio.
DR PRO; PR:Q969F2; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q969F2; protein.
DR Bgee; ENSG00000145506; Expressed in upper lobe of left lung and 90 other tissues.
DR Genevisible; Q969F2; HS.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:BHF-UCL.
DR GO; GO:0071944; C:cell periphery; IDA:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:BHF-UCL.
DR GO; GO:0070382; C:exocytic vesicle; IDA:CAFA.
DR GO; GO:0016328; C:lateral plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:CAFA.
DR GO; GO:0051117; F:ATPase binding; IPI:CAFA.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0019838; F:growth factor binding; IPI:BHF-UCL.
DR GO; GO:0032036; F:myosin heavy chain binding; IPI:CAFA.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0006887; P:exocytosis; IEA:UniProtKB-KW.
DR GO; GO:0048210; P:Golgi vesicle fusion to target membrane; IMP:BHF-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:BHF-UCL.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:BHF-UCL.
DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IDA:BHF-UCL.
DR GO; GO:0010954; P:positive regulation of protein processing; IDA:BHF-UCL.
DR GO; GO:0072659; P:protein localization to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR DisProt; DP00520; -.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR040140; Nkd-like.
DR PANTHER; PTHR22611; PTHR22611; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Cell membrane; Cytoplasm;
KW Cytoplasmic vesicle; Exocytosis; Lipoprotein; Membrane; Metal-binding;
KW Myristate; Reference proteome; Transport; Ubl conjugation;
KW Wnt signaling pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:15064403"
FT CHAIN 2..451
FT /note="Protein naked cuticle homolog 2"
FT /id="PRO_0000301993"
FT DOMAIN 119..154
FT /note="EF-hand"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT REGION 1..108
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..173
FT /note="Targeting to the basolateral cell membrane"
FT REGION 113..178
FT /note="Interaction with DVL1, DVL2 and DVL3"
FT /evidence="ECO:0000250"
FT REGION 162..237
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 256..408
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 300..385
FT /note="Interaction with TGFA"
FT COMPBIAS 34..60
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 73..96
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 185..220
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 283..302
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 368..382
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000305"
FT BINDING 134
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000305"
FT BINDING 138
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000305"
FT BINDING 143
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000305"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000269|PubMed:15064403"
FT VAR_SEQ 265..311
FT /note="PPVQAKQEPQGRASHLQARSRSQEPDTHAVHHRRSQVLVEHVVPASE -> Q
FT LCEKRSSAPRTHSGDKARGVGLCRELWSQAGHPQWPGPFPSGLVAV (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_027900"
FT VAR_SEQ 312..451
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_027901"
FT VARIANT 257
FT /note="T -> K (in dbSNP:rs35679233)"
FT /id="VAR_034934"
FT MUTAGEN 2
FT /note="G->A: Abrogates myristoylation and membrane
FT association and impairs delivery of TGFA to the cell
FT surface."
FT /evidence="ECO:0000269|PubMed:15064403"
SQ SEQUENCE 451 AA; 50055 MW; F27E708F9FAD1F2A CRC64;
MGKLQSKHAA AARKRRESPE GDSFVASAYA SGRKGAEEAE RRARDKQELP NGDPKEGPFR
EDQCPLQVAL PAEKAEGREH PGQLLSADDG ERAANREGPR GPGGQRLNID ALQCDVSVEE
DDRQEWTFTL YDFDNCGKVT REDMSSLMHT IYEVVDASVN HSSGSSKTLR VKLTVSPEPS
SKRKEGPPAG QDREPTRCRM EGELAEEPRV ADRRLSAHVR RPSTDPQPCS ERGPYCVDEN
TERRNHYLDL AGIENYTSRF GPGSPPVQAK QEPQGRASHL QARSRSQEPD THAVHHRRSQ
VLVEHVVPAS EPAARALDTQ PRPKGPEKQF LKSPKGSGKP PGVPASSKSG KAFSYYLPAV
LPPQAPQDGH HLPQPPPPPY GHKRYRQKGR EGHSPLKAPH AQPATVEHEV VRDLPPTPAG
EGYAVPVIQR HEHHHHHEHH HHHHHHHFHP S
