CLCF1_HUMAN
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 03-AUG-2022, entry version 167.
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 AlphaFoldDB; Q9UBD9; -.
DR SMR; Q9UBD9; -.
DR BioGRID; 117075; 38.
DR DIP; DIP-61204N; -.
DR IntAct; Q9UBD9; 6.
DR STRING; 9606.ENSP00000309338; -.
DR GlyGen; Q9UBD9; 1 site.
DR iPTMnet; Q9UBD9; -.
DR PhosphoSitePlus; Q9UBD9; -.
DR BioMuta; CLCF1; -.
DR DMDM; 56404673; -.
DR MassIVE; Q9UBD9; -.
DR PaxDb; Q9UBD9; -.
DR PeptideAtlas; Q9UBD9; -.
DR PRIDE; Q9UBD9; -.
DR ProteomicsDB; 4723; -.
DR ProteomicsDB; 83951; -. [Q9UBD9-1]
DR Antibodypedia; 44555; 251 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 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; NYQAYSH; -.
DR OrthoDB; 1278694at2759; -.
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 1083 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 122 other tissues.
DR Genevisible; Q9UBD9; HS.
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: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; PTHR21353; 1.
DR Pfam; PF06875; PRF; 1.
DR SUPFAM; SSF47266; SSF47266; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytokine; Disease variant; Glycoprotein;
KW 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"
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
