ID   CRDL2_HUMAN             Reviewed;         429 AA.
AC   Q6WN34; A5PKU9; Q6WN30; Q6WN31; Q6WN32; Q7Z5J3;
DT   26-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2004, sequence version 1.
DT   27-MAR-2024, entry version 147.
DE   RecName: Full=Chordin-like protein 2;
DE   AltName: Full=Breast tumor novel factor 1;
DE            Short=BNF-1;
DE   AltName: Full=Chordin-related protein 2;
DE   Flags: Precursor;
GN   Name=CHRDL2; Synonyms=BNF1, CHL2; ORFNames=UNQ765/PRO1557;
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 2), FUNCTION, TISSUE SPECIFICITY, AND
RP   INDUCTION.
RX   PubMed=12853144; DOI=10.1016/s0378-1119(03)00563-8;
RA   Wu I., Moses M.A.;
RT   "BNF-1, a novel gene encoding a putative extracellular matrix protein, is
RT   overexpressed in tumor tissues.";
RL   Gene 311:105-110(2003).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5), FUNCTION,
RP   INTERACTION WITH BMPS, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP   ALTERNATIVE SPLICING.
RX   PubMed=15094188; DOI=10.1016/j.gene.2004.01.029;
RA   Oren A., Toporik A., Biton S., Almogy N., Eshel D., Bernstein J.,
RA   Savitsky K., Rotman G.;
RT   "hCHL2, a novel chordin-related gene, displays differential expression and
RT   complex alternative splicing in human tissues and during myoblast and
RT   osteoblast maturation.";
RL   Gene 331:17-31(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND INTERACTION
RP   WITH BMPS.
RX   PubMed=14660436; DOI=10.1242/dev.00901;
RA   Nakayama N., Han C.-Y.E., Cam L., Lee J.I., Pretorius J., Fisher S.,
RA   Rosenfeld R., Scully S., Nishinakamura R., Duryea D., Van G., Bolon B.,
RA   Yokota T., Zhang K.;
RT   "A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in
RT   chondrocytes of developing cartilage and osteoarthritic joint cartilage.";
RL   Development 131:229-240(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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   PROTEIN SEQUENCE OF 26-40.
RX   PubMed=15340161; DOI=10.1110/ps.04682504;
RA   Zhang Z., Henzel W.J.;
RT   "Signal peptide prediction based on analysis of experimentally verified
RT   cleavage sites.";
RL   Protein Sci. 13:2819-2824(2004).
RN   [7]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-114.
RC   TISSUE=Milk;
RX   PubMed=18780401; DOI=10.1002/pmic.200701057;
RA   Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT   "Identification of N-linked glycoproteins in human milk by hydrophilic
RT   interaction liquid chromatography and mass spectrometry.";
RL   Proteomics 8:3833-3847(2008).
RN   [8]
RP   PHOSPHORYLATION AT SER-182.
RX   PubMed=26091039; DOI=10.1016/j.cell.2015.05.028;
RA   Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J.,
RA   Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N.,
RA   Pinna L.A., Pagliarini D.J., Dixon J.E.;
RT   "A single kinase generates the majority of the secreted phosphoproteome.";
RL   Cell 161:1619-1632(2015).
CC   -!- FUNCTION: May inhibit BMPs activity by blocking their interaction with
CC       their receptors. Has a negative regulator effect on the cartilage
CC       formation/regeneration from immature mesenchymal cells, by preventing
CC       or reducing the rate of matrix accumulation (By similarity). Implicated
CC       in tumor angiogenesis. May play a role during myoblast and osteoblast
CC       differentiation, and maturation. {ECO:0000250,
CC       ECO:0000269|PubMed:12853144, ECO:0000269|PubMed:15094188}.
CC   -!- SUBUNIT: Interacts with GDF5 (By similarity). May interact with BMP2,
CC       BMP4, BMP5, BMP6, BMP7 and INHBA. {ECO:0000250,
CC       ECO:0000269|PubMed:14660436, ECO:0000269|PubMed:15094188}.
CC   -!- INTERACTION:
CC       Q6WN34-2; Q8N9N5-2: BANP; NbExp=3; IntAct=EBI-12593838, EBI-11524452;
CC       Q6WN34-2; Q9H2X0: CHRD; NbExp=3; IntAct=EBI-12593838, EBI-947551;
CC       Q6WN34-2; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-12593838, EBI-744099;
CC       Q6WN34-2; P16930: FAH; NbExp=3; IntAct=EBI-12593838, EBI-4397076;
CC       Q6WN34-2; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-12593838, EBI-6658203;
CC       Q6WN34-2; Q9Y4H4: GPSM3; NbExp=3; IntAct=EBI-12593838, EBI-347538;
CC       Q6WN34-2; P49639: HOXA1; NbExp=3; IntAct=EBI-12593838, EBI-740785;
CC       Q6WN34-2; Q9UPY8: MAPRE3; NbExp=3; IntAct=EBI-12593838, EBI-726739;
CC       Q6WN34-2; P32242: OTX1; NbExp=3; IntAct=EBI-12593838, EBI-740446;
CC       Q6WN34-2; Q92569: PIK3R3; NbExp=3; IntAct=EBI-12593838, EBI-79893;
CC       Q6WN34-2; Q12837: POU4F2; NbExp=3; IntAct=EBI-12593838, EBI-17236143;
CC       Q6WN34-2; O75093: SLIT1; NbExp=3; IntAct=EBI-12593838, EBI-947791;
CC       Q6WN34-2; Q8TAU3: ZNF417; NbExp=3; IntAct=EBI-12593838, EBI-740727;
CC       Q6WN34-2; Q96SQ5: ZNF587; NbExp=3; IntAct=EBI-12593838, EBI-6427977;
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Secreted {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 4]: Cytoplasm {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasm {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC         Comment=Five additional mRNAs also exist. Differential expression of
CC         isoforms was observed during myoblast and osteoblast differentiation
CC         and maturation.;
CC       Name=1; Synonyms=I;
CC         IsoId=Q6WN34-1; Sequence=Displayed;
CC       Name=2; Synonyms=II;
CC         IsoId=Q6WN34-2; Sequence=VSP_013519;
CC       Name=3; Synonyms=VII;
CC         IsoId=Q6WN34-3; Sequence=VSP_013512, VSP_013513, VSP_013514,
CC                                  VSP_013518;
CC       Name=4; Synonyms=VIII;
CC         IsoId=Q6WN34-4; Sequence=VSP_013512, VSP_013513, VSP_013517,
CC                                  VSP_013518;
CC       Name=5; Synonyms=IX;
CC         IsoId=Q6WN34-5; Sequence=VSP_013512, VSP_013513, VSP_013515,
CC                                  VSP_013516;
CC   -!- TISSUE SPECIFICITY: Highly expressed in uterus. Moderately expressed in
CC       heart, liver, prostate, testis and ovary. Weakly expressed in skeletal
CC       muscle, kidney, spleen, small intestine and colon. Expressed in the
CC       secretory epithelial cells of uterine endometrium, fallopian tubes,
CC       endocervical glands, bladder and prostate, as well as the transitional
CC       epithelium of the urinary bladder, and in bone osteoblasts (at protein
CC       level). In normal cartilage, expression was confined in a few
CC       chondrocytes in the superficial zone as well as in the middle zone. In
CC       diseased cartilage coming from osteoarthritic patients, expression was
CC       limited to the middle zone of chondrocytes. Isoform 1 and isoform 2 are
CC       expressed in fetal cerebellum and heart, while only isoform 2 is
CC       detected in fetal spleen. Isoform 2 present in plasma.
CC       {ECO:0000269|PubMed:12853144, ECO:0000269|PubMed:14660436,
CC       ECO:0000269|PubMed:15094188}.
CC   -!- INDUCTION: Up-regulated in breast tumors but also in lung and colon
CC       tumors. {ECO:0000269|PubMed:12853144}.
CC   -!- PTM: Phosphorylated by FAM20C in the extracellular medium.
CC       {ECO:0000269|PubMed:26091039}.
CC   -!- CAUTION: According to PubMed:14660436, interacts with BMP2, BMP4, BMP5,
CC       BMP6, BMP7 but not INHBA. According to PubMed:15094188, interacts with
CC       INHBA but not BMP2, BMP4 and BMP6. {ECO:0000305}.
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DR   EMBL; AY163868; AAO31809.1; -; mRNA.
DR   EMBL; AY279090; AAQ19179.1; -; mRNA.
DR   EMBL; AY279092; AAQ19181.1; -; mRNA.
DR   EMBL; AY279093; AAQ19182.1; -; mRNA.
DR   EMBL; AY279094; AAQ19183.1; -; mRNA.
DR   EMBL; AX140199; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; AY358522; AAQ88886.1; -; mRNA.
DR   EMBL; BC142623; AAI42624.1; -; mRNA.
DR   CCDS; CCDS60893.1; -. [Q6WN34-1]
DR   CCDS; CCDS8234.1; -. [Q6WN34-2]
DR   RefSeq; NP_001265402.1; NM_001278473.2. [Q6WN34-1]
DR   RefSeq; NP_001291319.1; NM_001304390.1.
DR   RefSeq; NP_001291320.1; NM_001304391.1.
DR   RefSeq; NP_001291344.1; NM_001304415.1.
DR   RefSeq; NP_001291345.1; NM_001304416.1.
DR   RefSeq; NP_001291346.1; NM_001304417.1.
DR   RefSeq; NP_056239.3; NM_015424.5. [Q6WN34-2]
DR   AlphaFoldDB; Q6WN34; -.
DR   SMR; Q6WN34; -.
DR   BioGRID; 117395; 114.
DR   CORUM; Q6WN34; -.
DR   IntAct; Q6WN34; 15.
DR   STRING; 9606.ENSP00000263671; -.
DR   GlyConnect; 2935; 23 N-Linked glycans (1 site).
DR   GlyCosmos; Q6WN34; 2 sites, 28 glycans.
DR   GlyGen; Q6WN34; 8 sites, 27 N-linked glycans (1 site), 2 O-linked glycans (7 sites).
DR   iPTMnet; Q6WN34; -.
DR   PhosphoSitePlus; Q6WN34; -.
DR   BioMuta; CHRDL2; -.
DR   DMDM; 62900089; -.
DR   jPOST; Q6WN34; -.
DR   MassIVE; Q6WN34; -.
DR   PaxDb; 9606-ENSP00000263671; -.
DR   PeptideAtlas; Q6WN34; -.
DR   ProteomicsDB; 67768; -. [Q6WN34-1]
DR   ProteomicsDB; 67769; -. [Q6WN34-2]
DR   ProteomicsDB; 67770; -. [Q6WN34-3]
DR   ProteomicsDB; 67771; -. [Q6WN34-4]
DR   ProteomicsDB; 67772; -. [Q6WN34-5]
DR   Antibodypedia; 17275; 175 antibodies from 22 providers.
DR   DNASU; 25884; -.
DR   Ensembl; ENST00000263671.9; ENSP00000263671.5; ENSG00000054938.17. [Q6WN34-2]
DR   Ensembl; ENST00000376332.8; ENSP00000365510.3; ENSG00000054938.17. [Q6WN34-1]
DR   Ensembl; ENST00000528471.1; ENSP00000434589.1; ENSG00000054938.17. [Q6WN34-5]
DR   Ensembl; ENST00000534276.5; ENSP00000432055.1; ENSG00000054938.17. [Q6WN34-4]
DR   GeneID; 25884; -.
DR   KEGG; hsa:25884; -.
DR   MANE-Select; ENST00000376332.8; ENSP00000365510.3; NM_001278473.3; NP_001265402.1.
DR   UCSC; uc001ovh.5; human. [Q6WN34-1]
DR   AGR; HGNC:24168; -.
DR   CTD; 25884; -.
DR   DisGeNET; 25884; -.
DR   GeneCards; CHRDL2; -.
DR   HGNC; HGNC:24168; CHRDL2.
DR   HPA; ENSG00000054938; Tissue enhanced (endometrium, gallbladder, lymphoid tissue, smooth muscle).
DR   MIM; 613127; gene.
DR   neXtProt; NX_Q6WN34; -.
DR   OpenTargets; ENSG00000054938; -.
DR   PharmGKB; PA134883081; -.
DR   VEuPathDB; HostDB:ENSG00000054938; -.
DR   GeneTree; ENSGT00940000161241; -.
DR   HOGENOM; CLU_048288_1_1_1; -.
DR   InParanoid; Q6WN34; -.
DR   OMA; TEPQRCC; -.
DR   OrthoDB; 3670395at2759; -.
DR   PhylomeDB; Q6WN34; -.
DR   TreeFam; TF106451; -.
DR   PathwayCommons; Q6WN34; -.
DR   SignaLink; Q6WN34; -.
DR   BioGRID-ORCS; 25884; 16 hits in 1148 CRISPR screens.
DR   ChiTaRS; CHRDL2; human.
DR   GenomeRNAi; 25884; -.
DR   Pharos; Q6WN34; Tbio.
DR   PRO; PR:Q6WN34; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q6WN34; Protein.
DR   Bgee; ENSG00000054938; Expressed in smooth muscle tissue and 106 other cell types or tissues.
DR   ExpressionAtlas; Q6WN34; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR   GO; GO:0036122; F:BMP binding; IBA:GO_Central.
DR   GO; GO:0051216; P:cartilage development; IEA:UniProtKB-KW.
DR   GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR   GO; GO:0030514; P:negative regulation of BMP signaling pathway; IBA:GO_Central.
DR   GO; GO:0001503; P:ossification; IEA:UniProtKB-KW.
DR   Gene3D; 6.20.200.20; -; 1.
DR   Gene3D; 2.10.70.10; Complement Module, domain 1; 2.
DR   InterPro; IPR045717; CHRDL1/2.
DR   InterPro; IPR045716; CHRDL_1/2_C.
DR   InterPro; IPR001007; VWF_dom.
DR   PANTHER; PTHR46303:SF3; CHORDIN-LIKE PROTEIN 2; 1.
DR   PANTHER; PTHR46303; VWFC DOMAIN-CONTAINING PROTEIN; 1.
DR   Pfam; PF19548; CHRDL_1_2_C; 1.
DR   Pfam; PF00093; VWC; 3.
DR   SMART; SM00214; VWC; 3.
DR   SUPFAM; SSF57603; FnI-like domain; 3.
DR   PROSITE; PS01208; VWFC_1; 3.
DR   PROSITE; PS50184; VWFC_2; 3.
DR   Genevisible; Q6WN34; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Chondrogenesis; Cytoplasm; Developmental protein;
KW   Differentiation; Direct protein sequencing; Glycoprotein; Osteogenesis;
KW   Phosphoprotein; Reference proteome; Repeat; Secreted; Signal.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000269|PubMed:15340161"
FT   CHAIN           26..429
FT                   /note="Chordin-like protein 2"
FT                   /id="PRO_0000005371"
FT   DOMAIN          31..96
FT                   /note="VWFC 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00220"
FT   DOMAIN          109..175
FT                   /note="VWFC 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00220"
FT   DOMAIN          250..315
FT                   /note="VWFC 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00220"
FT   REGION          182..224
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         182
FT                   /note="Phosphoserine; by FAM20C"
FT                   /evidence="ECO:0000269|PubMed:26091039"
FT   CARBOHYD        114
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:18780401"
FT   VAR_SEQ         1..20
FT                   /note="Missing (in isoform 3, isoform 4 and isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013512"
FT   VAR_SEQ         21..28
FT                   /note="LDSHARAR -> MALVGLPG (in isoform 3, isoform 4 and
FT                   isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013513"
FT   VAR_SEQ         66..162
FT                   /note="GAHVSCYRLHCPPVHCPQPVTEPQQCCPKCVEPHTPSGLRAPPKSCQHNGTM
FT                   YQHGEIFSAHELFPSRLPNQCVLCSCTEGQIYCGLTTCPEPGCPA -> NLTLPLDSGP
FT                   HQSPASTTGPCTNTERSSVPMSCSPPACPTSVSSAAAQRARSTAASQPAPNQAAQHPSR
FT                   CQTPAAKPAKMRQVSNRMKRTVCSRSMG (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013514"
FT   VAR_SEQ         66..113
FT                   /note="GAHVSCYRLHCPPVHCPQPVTEPQQCCPKCVEPHTPSGLRAPPKSCQH ->
FT                   NLTLPLDSGPHQSPASTTGPCTNTERSSVPMSCSPPACPTSVSSAAAQ (in
FT                   isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013515"
FT   VAR_SEQ         114..429
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013516"
FT   VAR_SEQ         145..162
FT                   /note="EGQIYCGLTTCPEPGCPA -> MRQVSNRMKRTVCSRSMG (in isoform
FT                   4)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013517"
FT   VAR_SEQ         163..429
FT                   /note="Missing (in isoform 3 and isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013518"
FT   VAR_SEQ         374..426
FT                   /note="GIFHLTQIKKVRKQDFQKEAQHFRLLAGPHEGHWNVFLAQTLELKVTASPDK
FT                   V -> DEETEAQRGEVPGPRPHSQNLPLDSDQESQEARLPERGTALPTARWPPRRSLER
FT                   LPSPDPGAEGHGQSRQSDQDI (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12853144,
FT                   ECO:0000303|PubMed:12975309, ECO:0000303|PubMed:15094188"
FT                   /id="VSP_013519"
FT   VARIANT         335
FT                   /note="P -> L (in dbSNP:rs35903991)"
FT                   /id="VAR_055651"
FT   CONFLICT        187
FT                   /note="S -> R (in Ref. 2; AX140199)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        231
FT                   /note="R -> I (in Ref. 2; AX140199)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   429 AA;  47495 MW;  A8111F26B2EF96A4 CRC64;
     MVPEVRVLSS LLGLALLWFP LDSHARARPD MFCLFHGKRY SPGESWHPYL EPQGLMYCLR
     CTCSEGAHVS CYRLHCPPVH CPQPVTEPQQ CCPKCVEPHT PSGLRAPPKS CQHNGTMYQH
     GEIFSAHELF PSRLPNQCVL CSCTEGQIYC GLTTCPEPGC PAPLPLPDSC CQACKDEASE
     QSDEEDSVQS LHGVRHPQDP CSSDAGRKRG PGTPAPTGLS APLSFIPRHF RPKGAGSTTV
     KIVLKEKHKK ACVHGGKTYS HGEVWHPAFR AFGPLPCILC TCEDGRQDCQ RVTCPTEYPC
     RHPEKVAGKC CKICPEDKAD PGHSEISSTR CPKAPGRVLV HTSVSPSPDN LRRFALEHEA
     SDLVEIYLWK LVKGIFHLTQ IKKVRKQDFQ KEAQHFRLLA GPHEGHWNVF LAQTLELKVT
     ASPDKVTKT
//