ID   CLCF1_HUMAN             Reviewed;         225 AA.
AC   Q9UBD9; B4DNT4; Q6NZA4;
DT   07-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   27-MAR-2024, entry version 176.
DE   RecName: Full=Cardiotrophin-like cytokine factor 1;
DE   AltName: Full=B-cell-stimulating factor 3;
DE            Short=BSF-3;
DE   AltName: Full=Novel neurotrophin-1;
DE            Short=NNT-1;
DE   Flags: Precursor;
GN   Name=CLCF1; Synonyms=BSF3, CLC, NNT1;
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] (ISOFORM 1), FUNCTION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=10500198; DOI=10.1073/pnas.96.20.11458;
RA   Senaldi G., Varnum B.C., Sarmiento U., Starnes C., Lile J., Scully S.,
RA   Guo J., Elliott G., McNinch J., Shaklee C.L., Freeman D., Manu F.,
RA   Simonet W.S., Boone T., Chang M.-S.;
RT   "Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6
RT   family.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:11458-11463(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=10448081; DOI=10.1006/bbrc.1999.1181;
RA   Shi Y., Wang W., Yourey P.A., Gohari S., Zukauskas D., Zhang J., Ruben S.,
RA   Alderson R.F.;
RT   "Computational EST database analysis identifies a novel member of the
RT   neuropoietic cytokine family.";
RL   Biochem. Biophys. Res. Commun. 262:132-138(1999).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA   Hu X., Xu Y., Zhang B., Peng X., Yuan J., Qiang B.;
RL   Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Lung;
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Kidney;
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   [8]
RP   FUNCTION, AND INTERACTION WITH CRLF1; CNTFR AND SORL1.
RX   PubMed=26858303; DOI=10.1128/mcb.00917-15;
RA   Larsen J.V., Kristensen A.M., Pallesen L.T., Bauer J., Vaegter C.B.,
RA   Nielsen M.S., Madsen P., Petersen C.M.;
RT   "Cytokine-like factor 1, an essential facilitator of cardiotrophin-like
RT   cytokine:ciliary neurotrophic factor receptor alpha signaling and sorLA-
RT   mediated turnover.";
RL   Mol. Cell. Biol. 36:1272-1286(2016).
RN   [9]
RP   VARIANT CISS2 LEU-197, AND CHARACTERIZATION OF VARIANT CISS2 LEU-197.
RX   PubMed=16782820; DOI=10.1073/pnas.0509598103;
RA   Rousseau F., Gauchat J.-F., McLeod J.G., Chevalier S., Guillet C.,
RA   Guilhot F., Cognet I., Froger J., Hahn A.F., Knappskog P.M., Gascan H.,
RA   Boman H.;
RT   "Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary
RT   neurotrophic factor receptor, leads to cold-induced sweating syndrome in a
RT   patient.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:10068-10073(2006).
CC   -!- FUNCTION: In complex with CRLF1, forms a heterodimeric neurotropic
CC       cytokine that plays a crucial role during neuronal development
CC       (Probable). Also stimulates B-cells. Binds to and activates the
CC       ILST/gp130 receptor. {ECO:0000269|PubMed:10448081,
CC       ECO:0000269|PubMed:10500198, ECO:0000305|PubMed:26858303}.
CC   -!- SUBUNIT: Forms a heteromeric complex with cardiotrophin-like cytokine
CC       CRLF1/CLF-1; the CRLF1-CLCF1 complex is a ligand for the ciliary
CC       neurotrophic factor receptor/CNTFR (PubMed:26858303). The CRLF1-CLCF1
CC       heterodimer binds SORL1 (via N-terminal ectodomain); within this
CC       complex, the interaction is mediated predominantly by the CRLF1 moiety
CC       (PubMed:26858303). The tripartite signaling complex formed by CRLF1,
CC       CLCF1 and CNTFR also binds SORL1 (PubMed:26858303).
CC       {ECO:0000269|PubMed:26858303}.
CC   -!- INTERACTION:
CC       Q9UBD9; P02649: APOE; NbExp=3; IntAct=EBI-2880701, EBI-1222467;
CC       PRO_0000015616; P26992: CNTFR; NbExp=3; IntAct=EBI-25298664, EBI-743758;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q9UBD9-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9UBD9-2; Sequence=VSP_044269;
CC   -!- TISSUE SPECIFICITY: Expressed predominantly in lymph nodes, spleen,
CC       peripheral blood lymphocytes, bone marrow, and fetal liver.
CC       {ECO:0000269|PubMed:10448081, ECO:0000269|PubMed:10500198}.
CC   -!- DISEASE: Crisponi/Cold-induced sweating syndrome 2 (CISS2)
CC       [MIM:610313]: An autosomal recessive disorder characterized by profuse
CC       sweating induced by cool surroundings (temperatures of 7 to 18 degrees
CC       Celsius). Patients manifest, in the neonatal period, orofacial weakness
CC       with impaired sucking and swallowing, resulting in poor feeding.
CC       Affected infants show a tendency to startle, with contractions of the
CC       facial muscles in response to tactile stimuli or during crying,
CC       trismus, abundant salivation, and opisthotonus. These features are
CC       referred to as Crisponi syndrome and can result in early death in
CC       infancy. Patients who survive into childhood have hyperhidrosis, mainly
CC       of the upper body, in response to cold temperatures, and sweat very
CC       little with heat. Additional abnormalities include a high-arched
CC       palate, nasal voice, depressed nasal bridge, inability to fully extend
CC       the elbows and kyphoscoliosis. {ECO:0000269|PubMed:16782820}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}.
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DR   EMBL; AF176911; AAF00991.1; -; mRNA.
DR   EMBL; AF176912; AAF00992.1; -; Genomic_DNA.
DR   EMBL; AF172854; AAD54284.1; -; mRNA.
DR   EMBL; AY049779; AAL15436.1; -; mRNA.
DR   EMBL; AK298052; BAG60346.1; -; mRNA.
DR   EMBL; AP003419; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471076; EAW74601.1; -; Genomic_DNA.
DR   EMBL; BC012939; AAH12939.1; -; mRNA.
DR   EMBL; BC066229; AAH66229.1; -; mRNA.
DR   EMBL; BC066230; AAH66230.1; -; mRNA.
DR   EMBL; BC066231; AAH66231.1; -; mRNA.
DR   CCDS; CCDS31617.1; -. [Q9UBD9-1]
DR   CCDS; CCDS53666.1; -. [Q9UBD9-2]
DR   RefSeq; NP_001159684.1; NM_001166212.1. [Q9UBD9-2]
DR   RefSeq; NP_037378.1; NM_013246.2. [Q9UBD9-1]
DR   PDB; 8D7H; EM; 3.40 A; D/H=28-225.
DR   PDB; 8D7R; EM; 3.90 A; D=28-225.
DR   PDBsum; 8D7H; -.
DR   PDBsum; 8D7R; -.
DR   AlphaFoldDB; Q9UBD9; -.
DR   EMDB; EMD-27230; -.
DR   EMDB; EMD-27231; -.
DR   SMR; Q9UBD9; -.
DR   BioGRID; 117075; 41.
DR   DIP; DIP-61204N; -.
DR   IntAct; Q9UBD9; 6.
DR   STRING; 9606.ENSP00000309338; -.
DR   GlyCosmos; Q9UBD9; 1 site, No reported glycans.
DR   GlyGen; Q9UBD9; 1 site.
DR   iPTMnet; Q9UBD9; -.
DR   PhosphoSitePlus; Q9UBD9; -.
DR   BioMuta; CLCF1; -.
DR   DMDM; 56404673; -.
DR   MassIVE; Q9UBD9; -.
DR   PaxDb; 9606-ENSP00000309338; -.
DR   PeptideAtlas; Q9UBD9; -.
DR   ProteomicsDB; 4723; -.
DR   ProteomicsDB; 83951; -. [Q9UBD9-1]
DR   Antibodypedia; 44555; 280 antibodies from 26 providers.
DR   DNASU; 23529; -.
DR   Ensembl; ENST00000312438.8; ENSP00000309338.7; ENSG00000175505.11. [Q9UBD9-1]
DR   Ensembl; ENST00000533438.1; ENSP00000434122.1; ENSG00000175505.11. [Q9UBD9-2]
DR   GeneID; 23529; -.
DR   KEGG; hsa:23529; -.
DR   MANE-Select; ENST00000312438.8; ENSP00000309338.7; NM_013246.3; NP_037378.1.
DR   UCSC; uc001okq.4; human. [Q9UBD9-1]
DR   AGR; HGNC:17412; -.
DR   CTD; 23529; -.
DR   DisGeNET; 23529; -.
DR   GeneCards; CLCF1; -.
DR   GeneReviews; CLCF1; -.
DR   HGNC; HGNC:17412; CLCF1.
DR   HPA; ENSG00000175505; Low tissue specificity.
DR   MalaCards; CLCF1; -.
DR   MIM; 607672; gene.
DR   MIM; 610313; phenotype.
DR   neXtProt; NX_Q9UBD9; -.
DR   OpenTargets; ENSG00000175505; -.
DR   Orphanet; 157820; Cold-induced sweating syndrome.
DR   Orphanet; 1545; Crisponi syndrome.
DR   PharmGKB; PA142672106; -.
DR   VEuPathDB; HostDB:ENSG00000175505; -.
DR   eggNOG; ENOG502QUIA; Eukaryota.
DR   GeneTree; ENSGT00510000048856; -.
DR   HOGENOM; CLU_079382_0_0_1; -.
DR   InParanoid; Q9UBD9; -.
DR   OMA; QEWHSLN; -.
DR   OrthoDB; 4253899at2759; -.
DR   PhylomeDB; Q9UBD9; -.
DR   TreeFam; TF333266; -.
DR   PathwayCommons; Q9UBD9; -.
DR   Reactome; R-HSA-6788467; IL-6-type cytokine receptor ligand interactions.
DR   SignaLink; Q9UBD9; -.
DR   SIGNOR; Q9UBD9; -.
DR   BioGRID-ORCS; 23529; 12 hits in 1160 CRISPR screens.
DR   ChiTaRS; CLCF1; human.
DR   GeneWiki; CLCF1; -.
DR   GenomeRNAi; 23529; -.
DR   Pharos; Q9UBD9; Tbio.
DR   PRO; PR:Q9UBD9; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q9UBD9; Protein.
DR   Bgee; ENSG00000175505; Expressed in left uterine tube and 123 other cell types or tissues.
DR   GO; GO:0097059; C:CNTFR-CLCF1 complex; IDA:BHF-UCL.
DR   GO; GO:0097058; C:CRLF-CLCF1 complex; IDA:BHF-UCL.
DR   GO; GO:0005576; C:extracellular region; IDA:BHF-UCL.
DR   GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR   GO; GO:0005127; F:ciliary neurotrophic factor receptor binding; IDA:BHF-UCL.
DR   GO; GO:0005125; F:cytokine activity; NAS:UniProtKB.
DR   GO; GO:0008083; F:growth factor activity; TAS:HGNC-UCL.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:HGNC-UCL.
DR   GO; GO:0030183; P:B cell differentiation; ISS:BHF-UCL.
DR   GO; GO:0007166; P:cell surface receptor signaling pathway; ISS:BHF-UCL.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; NAS:UniProtKB.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:BHF-UCL.
DR   GO; GO:0048711; P:positive regulation of astrocyte differentiation; ISS:BHF-UCL.
DR   GO; GO:0030890; P:positive regulation of B cell proliferation; ISS:BHF-UCL.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR   GO; GO:0002639; P:positive regulation of immunoglobulin production; ISS:BHF-UCL.
DR   GO; GO:0048295; P:positive regulation of isotype switching to IgE isotypes; ISS:BHF-UCL.
DR   GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:BHF-UCL.
DR   GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; ISS:BHF-UCL.
DR   Gene3D; 1.20.1250.10; -; 1.
DR   InterPro; IPR009079; 4_helix_cytokine-like_core.
DR   InterPro; IPR010681; PRF/CT.
DR   PANTHER; PTHR21353; -; 1.
DR   PANTHER; PTHR21353:SF7; CARDIOTROPHIN-LIKE CYTOKINE FACTOR 1; 1.
DR   Pfam; PF06875; PRF; 1.
DR   SUPFAM; SSF47266; 4-helical cytokines; 1.
DR   Genevisible; Q9UBD9; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cytokine; Disease variant;
KW   Glycoprotein; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..27
FT                   /evidence="ECO:0000255"
FT   CHAIN           28..225
FT                   /note="Cardiotrophin-like cytokine factor 1"
FT                   /id="PRO_0000015616"
FT   CARBOHYD        29
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         1..10
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_044269"
FT   VARIANT         197
FT                   /note="R -> L (in CISS2; heterozygous compound with a
FT                   nonsense mutation; unable to bind CNTFR alpha;
FT                   dbSNP:rs104894203)"
FT                   /evidence="ECO:0000269|PubMed:16782820"
FT                   /id="VAR_028354"
FT   CONFLICT        23
FT                   /note="P -> L (in Ref. 7; AAH66231)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        218
FT                   /note="L -> P (in Ref. 7; AAH66231)"
FT                   /evidence="ECO:0000305"
FT   HELIX           36..65
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           68..70
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   STRAND          71..73
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           91..96
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           101..119
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           120..122
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           127..153
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   STRAND          165..169
FT                   /evidence="ECO:0007829|PDB:8D7H"
FT   HELIX           177..207
FT                   /evidence="ECO:0007829|PDB:8D7H"
SQ   SEQUENCE   225 AA;  25176 MW;  E2DD4B6280833B55 CRC64;
     MDLRAGDSWG MLACLCTVLW HLPAVPALNR TGDPGPGPSI QKTYDLTRYL EHQLRSLAGT
     YLNYLGPPFN EPDFNPPRLG AETLPRATVD LEVWRSLNDK LRLTQNYEAY SHLLCYLRGL
     NRQAATAELR RSLAHFCTSL QGLLGSIAGV MAALGYPLPQ PLPGTEPTWT PGPAHSDFLQ
     KMDDFWLLKE LQTWLWRSAK DFNRLKKKMQ PPAAAVTLHL GAHGF
//