ID   CFC1_HUMAN              Reviewed;         223 AA.
AC   P0CG37; B2RCY0; B9EJD3; Q53T05; Q9GZR3;
DT   13-JUL-2010, integrated into UniProtKB/Swiss-Prot.
DT   13-JUL-2010, sequence version 1.
DT   27-MAR-2024, entry version 98.
DE   RecName: Full=Cryptic protein;
DE   AltName: Full=Cryptic family protein 1;
DE   Flags: Precursor;
GN   Name=CFC1;
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 [GENOMIC DNA / MRNA], FUNCTION, VARIANT HTX2 CYS-112,
RP   CHARACTERIZATION OF VARIANT HTX2 CYS-112, AND VARIANTS TRP-78 AND CYS-189.
RX   PubMed=11062482; DOI=10.1038/81695;
RA   Bamford R.N., Roessler E., Burdine R.D., Saplakoglu U., dela Cruz J.,
RA   Splitt M., Towbin J., Bowers P., Marino B., Schier A.F., Shen M.M.,
RA   Muenke M., Casey B.;
RT   "Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with
RT   human left-right laterality defects.";
RL   Nat. Genet. 26:365-369(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Subthalamic nucleus;
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=15815621; DOI=10.1038/nature03466;
RA   Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA   Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA   Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA   Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA   Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA   Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA   Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA   Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA   Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA   McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA   Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA   Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA   Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA   Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA   Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA   Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA   Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA   Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA   Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA   Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA   Wilson R.K.;
RT   "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT   4.";
RL   Nature 434:724-731(2005).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, and Lung;
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   [5]
RP   SUBCELLULAR LOCATION, GPI-ANCHOR AT ASP-158, AND MUTAGENESIS OF
RP   151-GLY--LEU-223.
RX   PubMed=18930707; DOI=10.1016/j.bbamem.2008.09.011;
RA   Watanabe K., Nagaoka T., Strizzi L., Mancino M., Gonzales M., Bianco C.,
RA   Salomon D.S.;
RT   "Characterization of the glycosylphosphatidylinositol-anchor signal
RT   sequence of human Cryptic with a hydrophilic extension.";
RL   Biochim. Biophys. Acta 1778:2671-2681(2008).
RN   [6]
RP   VARIANT TRP-78, AND INVOLVEMENT IN HTX2.
RX   PubMed=11799476; DOI=10.1086/339079;
RA   Goldmuntz E., Bamford R., Karkera J.D., dela Cruz J., Roessler E.,
RA   Muenke M.;
RT   "CFC1 mutations in patients with transposition of the great arteries and
RT   double-outlet right ventricle.";
RL   Am. J. Hum. Genet. 70:776-780(2002).
CC   -!- FUNCTION: NODAL coreceptor involved in the correct establishment of the
CC       left-right axis. May play a role in mesoderm and/or neural patterning
CC       during gastrulation. {ECO:0000269|PubMed:11062482}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18930707};
CC       Lipid-anchor, GPI-anchor {ECO:0000269|PubMed:18930707}. Secreted
CC       {ECO:0000269|PubMed:18930707}. Note=Does not exhibit a typical GPI-
CC       signal sequence. The C-ter hydrophilic extension of the GPI-signal
CC       sequence reduces the efficiency of processing and could lead to the
CC       production of an secreted unprocessed form. This extension is found
CC       only in primates.
CC   -!- PTM: N-glycosylated. {ECO:0000250}.
CC   -!- DISEASE: Heterotaxy, visceral, 2, autosomal (HTX2) [MIM:605376]: A form
CC       of visceral heterotaxy, a complex disorder due to disruption of the
CC       normal left-right asymmetry of the thoracoabdominal organs. Visceral
CC       heterotaxy or situs ambiguus results in randomization of the placement
CC       of visceral organs, including the heart, lungs, liver, spleen, and
CC       stomach. The organs are oriented randomly with respect to the left-
CC       right axis and with respect to one another. It can be associated with a
CC       variety of congenital defects including cardiac malformations.
CC       {ECO:0000269|PubMed:11062482, ECO:0000269|PubMed:11799476}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.
CC       {ECO:0000305}.
CC   -!- CAUTION: This gene differs from CFC1B by only one residue at position
CC       78:R -> W. R78W is also thought to be a CFC1 polymorphism which has
CC       been shown to lead to a different cell surface distribution and
CC       activity (PubMed:11799476, PubMed:11062482). {ECO:0000305}.
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DR   EMBL; AF312769; AAG30294.1; -; mRNA.
DR   EMBL; AF312925; AAG42475.1; -; Genomic_DNA.
DR   EMBL; AK315326; BAG37727.1; -; mRNA.
DR   EMBL; AC140481; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC069508; AAH69508.1; -; mRNA.
DR   EMBL; BC074825; AAH74825.1; -; mRNA.
DR   EMBL; BC074826; AAH74826.1; -; mRNA.
DR   EMBL; BC110080; AAI10081.1; -; mRNA.
DR   EMBL; BC146897; AAI46898.1; -; mRNA.
DR   CCDS; CCDS2162.1; -.
DR   RefSeq; NP_001257349.1; NM_001270420.1.
DR   RefSeq; NP_001257350.1; NM_001270421.1.
DR   RefSeq; NP_115934.1; NM_032545.3.
DR   AlphaFoldDB; P0CG37; -.
DR   BioGRID; 121022; 151.
DR   STRING; 9606.ENSP00000259216; -.
DR   GlyCosmos; P0CG37; 1 site, No reported glycans.
DR   GlyGen; P0CG37; 1 site.
DR   iPTMnet; P0CG37; -.
DR   PhosphoSitePlus; P0CG37; -.
DR   BioMuta; CFC1; -.
DR   DMDM; 300680886; -.
DR   MassIVE; P0CG37; -.
DR   PaxDb; 9606-ENSP00000259216; -.
DR   PeptideAtlas; P0CG37; -.
DR   ProteomicsDB; 52467; -.
DR   ABCD; P0CG37; 8 sequenced antibodies.
DR   Antibodypedia; 33508; 260 antibodies from 30 providers.
DR   DNASU; 55997; -.
DR   Ensembl; ENST00000259216.6; ENSP00000259216.5; ENSG00000136698.10.
DR   GeneID; 55997; -.
DR   KEGG; hsa:55997; -.
DR   MANE-Select; ENST00000259216.6; ENSP00000259216.5; NM_032545.4; NP_115934.1.
DR   UCSC; uc002tro.3; human.
DR   AGR; HGNC:18292; -.
DR   CTD; 55997; -.
DR   DisGeNET; 55997; -.
DR   GeneCards; CFC1; -.
DR   HGNC; HGNC:18292; CFC1.
DR   HPA; ENSG00000136698; Tissue enhanced (brain, pancreas, pituitary gland).
DR   MalaCards; CFC1; -.
DR   MIM; 605194; gene.
DR   MIM; 605376; phenotype.
DR   neXtProt; NX_P0CG37; -.
DR   OpenTargets; ENSG00000136698; -.
DR   Orphanet; 244283; Biliary atresia with splenic malformation syndrome.
DR   Orphanet; 216729; Congenitally uncorrected transposition of the great arteries with cardiac malformation.
DR   Orphanet; 99042; Congenitally uncorrected transposition of the great arteries with coarctation.
DR   Orphanet; 216718; Isolated congenitally uncorrected transposition of the great arteries.
DR   Orphanet; 157769; Situs ambiguus.
DR   PharmGKB; PA134916180; -.
DR   VEuPathDB; HostDB:ENSG00000136698; -.
DR   eggNOG; KOG1217; Eukaryota.
DR   GeneTree; ENSGT00940000162302; -.
DR   HOGENOM; CLU_092661_0_0_1; -.
DR   InParanoid; P0CG37; -.
DR   OMA; PGSCDPK; -.
DR   OrthoDB; 2970545at2759; -.
DR   PhylomeDB; P0CG37; -.
DR   TreeFam; TF333187; -.
DR   PathwayCommons; P0CG37; -.
DR   Reactome; R-HSA-1181150; Signaling by NODAL.
DR   Reactome; R-HSA-1433617; Regulation of signaling by NODAL.
DR   BioGRID-ORCS; 55997; 27 hits in 1025 CRISPR screens.
DR   ChiTaRS; CFC1; human.
DR   GenomeRNAi; 55997; -.
DR   Pharos; P0CG37; Tbio.
DR   PRO; PR:P0CG37; -.
DR   Proteomes; UP000005640; Chromosome 2.
DR   RNAct; P0CG37; Protein.
DR   Bgee; ENSG00000136698; Expressed in islet of Langerhans and 61 other cell types or tissues.
DR   ExpressionAtlas; P0CG37; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR   GO; GO:0005576; C:extracellular region; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0070697; F:activin receptor binding; IBA:GO_Central.
DR   GO; GO:0038100; F:nodal binding; IPI:UniProtKB.
DR   GO; GO:0009952; P:anterior/posterior pattern specification; IBA:GO_Central.
DR   GO; GO:0001568; P:blood vessel development; IBA:GO_Central.
DR   GO; GO:0007368; P:determination of left/right symmetry; IBA:GO_Central.
DR   GO; GO:0007369; P:gastrulation; IEA:UniProtKB-KW.
DR   GO; GO:0007507; P:heart development; IBA:GO_Central.
DR   GO; GO:0038092; P:nodal signaling pathway; IMP:UniProtKB.
DR   CDD; cd00054; EGF_CA; 1.
DR   Gene3D; 2.10.25.10; Laminin; 1.
DR   InterPro; IPR019011; Cryptic/Cripto_CFC-dom.
DR   InterPro; IPR000742; EGF-like_dom.
DR   PANTHER; PTHR14949:SF25; CRYPTIC FAMILY PROTEIN 1B-RELATED; 1.
DR   PANTHER; PTHR14949; EGF-LIKE-DOMAIN, MULTIPLE 7, 8; 1.
DR   Pfam; PF09443; CFC; 1.
DR   SUPFAM; SSF57196; EGF/Laminin; 2.
DR   PROSITE; PS00022; EGF_1; 1.
DR   PROSITE; PS50026; EGF_3; 1.
DR   Genevisible; P0CG37; HS.
PE   1: Evidence at protein level;
KW   Cell membrane; Developmental protein; Disease variant; Disulfide bond;
KW   EGF-like domain; Gastrulation; Glycoprotein; GPI-anchor; Heterotaxy;
KW   Lipoprotein; Membrane; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000255"
FT   CHAIN           26..158
FT                   /note="Cryptic protein"
FT                   /id="PRO_0000044630"
FT   PROPEP          159..223
FT                   /note="Removed in mature form"
FT                   /id="PRO_0000395407"
FT   DOMAIN          86..115
FT                   /note="EGF-like"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   LIPID           158
FT                   /note="GPI-anchor amidated aspartate"
FT                   /evidence="ECO:0000269|PubMed:18930707"
FT   CARBOHYD        52
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        90..97
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DISULFID        91..103
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   DISULFID        105..114
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT   VARIANT         78
FT                   /note="R -> W (in dbSNP:rs2579433)"
FT                   /evidence="ECO:0000269|PubMed:11062482,
FT                   ECO:0000269|PubMed:11799476"
FT                   /id="VAR_024322"
FT   VARIANT         112
FT                   /note="R -> C (in HTX2; complete loss of activity; abnormal
FT                   cell surface localization; dbSNP:rs104893611)"
FT                   /evidence="ECO:0000269|PubMed:11062482"
FT                   /id="VAR_024323"
FT   VARIANT         189
FT                   /note="R -> C (in dbSNP:rs1350439781)"
FT                   /evidence="ECO:0000269|PubMed:11062482"
FT                   /id="VAR_024324"
FT   MUTAGEN         191..223
FT                   /note="LRPDAPAHPRSLVPSVLQRERRPCGRPGLGHRL->VVVVV: Does not
FT                   affect the cellular localization and the biological
FT                   activity."
FT   MUTAGEN         191..223
FT                   /note="Missing: Increased NODAL dependent signaling."
SQ   SEQUENCE   223 AA;  24612 MW;  B52852A00ABCF1A3 CRC64;
     MTWRHHVRLL FTVSLALQII NLGNSYQREK HNGGREEVTK VATQKHRQSP LNWTSSHFGE
     VTGSAEGWGP EEPLPYSRAF GEGASARPRC CRNGGTCVLG SFCVCPAHFT GRYCEHDQRR
     SECGALEHGA WTLRACHLCR CIFGALHCLP LQTPDRCDPK DFLASHAHGP SAGGAPSLLL
     LLPCALLHRL LRPDAPAHPR SLVPSVLQRE RRPCGRPGLG HRL
//