ID   INSL4_HUMAN             Reviewed;         139 AA.
AC   Q14641; A8K678; Q5W127;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   24-JAN-2024, entry version 170.
DE   RecName: Full=Early placenta insulin-like peptide;
DE            Short=EPIL;
DE   AltName: Full=Insulin-like peptide 4;
DE   AltName: Full=Placentin;
DE   Contains:
DE     RecName: Full=Early placenta insulin-like peptide B chain;
DE   Contains:
DE     RecName: Full=Early placenta insulin-like peptide A chain;
DE   Flags: Precursor;
GN   Name=INSL4;
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].
RC   TISSUE=Placenta;
RX   PubMed=8666396; DOI=10.1006/geno.1995.9980;
RA   Chassin D., Laurent A., Janneau J.-L., Berger R., Bellet D.;
RT   "Cloning of a new member of the insulin gene superfamily (INSL4) expressed
RT   in human placenta.";
RL   Genomics 29:465-470(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
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=15164053; DOI=10.1038/nature02465;
RA   Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA   Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA   Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA   Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA   Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA   Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA   Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA   Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA   Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA   Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA   Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA   Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA   Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA   Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA   Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA   Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA   Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA   Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA   McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA   Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA   Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA   Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA   Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA   West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA   Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA   Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA   Dunham I.;
RT   "DNA sequence and analysis of human chromosome 9.";
RL   Nature 429:369-374(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
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   PROTEOLYTIC PROCESSING.
RX   PubMed=9284764; DOI=10.1210/jcem.82.9.4359;
RA   Bellet D., Lavaissiere L., Mock P., Laurent A., Sabourin J.-C., Bedossa P.,
RA   Le Bouteiller P., Frydman R., Troalen F., Bidart J.-M.;
RT   "Identification of pro-EPIL and EPIL peptides translated from insulin-like
RT   4 (INSL4) mRNA in human placenta.";
RL   J. Clin. Endocrinol. Metab. 82:3169-3172(1997).
RN   [8]
RP   TISSUE SPECIFICITY.
RX   PubMed=9740319;
RX   DOI=10.1002/(sici)1098-2795(199810)51:2<123::aid-mrd1>3.0.co;2-s;
RA   Laurent A., Rouillac C., Delezoide A.-L., Giovangrandi Y., Vekemans M.,
RA   Bellet D., Abitbol M., Vidaud M.;
RT   "Insulin-like 4 (INSL4) gene expression in human embryonic and
RT   trophoblastic tissues.";
RL   Mol. Reprod. Dev. 51:123-129(1998).
RN   [9]
RP   TISSUE SPECIFICITY, AND POSSIBLE INVOLVEMENT IN INVASION/MIGRATION OF
RP   TROPHOBLAST CELLS.
RX   PubMed=12414911; DOI=10.1210/jc.2002-021093;
RA   Janneau J.-L., Maldonado-Estrada J., Tachdjian G., Miran I., Motte N.,
RA   Saulnier P., Sabourin J.-C., Cote J.-F., Simon B., Frydman R., Chaouat G.,
RA   Bellet D.;
RT   "Transcriptional expression of genes involved in cell invasion and
RT   migration by normal and tumoral trophoblast cells.";
RL   J. Clin. Endocrinol. Metab. 87:5336-5339(2002).
CC   -!- FUNCTION: May play an important role in trophoblast development and in
CC       the regulation of bone formation.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Expressed in placenta, uterus and in fetal
CC       perichondrium. Expression levels were increased in both early placentas
CC       and molar pregnancies and were reduced in choriocarcinoma cells.
CC       {ECO:0000269|PubMed:12414911, ECO:0000269|PubMed:9740319}.
CC   -!- DEVELOPMENTAL STAGE: Highly expressed in the early placenta. Expression
CC       of epil peptides in the villous cytotrophoblast is different from that
CC       displayed by the syncytiotrophoblast. In fetal tissues it was
CC       identified in the perichondrium of all four limbs, vertebrae, and ribs.
CC       It was abundant in interbone ligaments.
CC   -!- SIMILARITY: Belongs to the insulin family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; L34838; AAB08516.1; -; mRNA.
DR   EMBL; AK291543; BAF84232.1; -; mRNA.
DR   EMBL; AL133547; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471071; EAW58772.1; -; Genomic_DNA.
DR   EMBL; BC026254; AAH26254.1; -; mRNA.
DR   CCDS; CCDS6459.1; -.
DR   RefSeq; NP_002186.1; NM_002195.1.
DR   AlphaFoldDB; Q14641; -.
DR   BioGRID; 109852; 6.
DR   STRING; 9606.ENSP00000239316; -.
DR   GlyGen; Q14641; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q14641; -.
DR   PhosphoSitePlus; Q14641; -.
DR   BioMuta; INSL4; -.
DR   DMDM; 2497411; -.
DR   jPOST; Q14641; -.
DR   MassIVE; Q14641; -.
DR   MaxQB; Q14641; -.
DR   PaxDb; 9606-ENSP00000239316; -.
DR   PeptideAtlas; Q14641; -.
DR   Antibodypedia; 24117; 153 antibodies from 22 providers.
DR   DNASU; 3641; -.
DR   Ensembl; ENST00000239316.4; ENSP00000239316.4; ENSG00000120211.4.
DR   GeneID; 3641; -.
DR   KEGG; hsa:3641; -.
DR   MANE-Select; ENST00000239316.4; ENSP00000239316.4; NM_002195.2; NP_002186.1.
DR   UCSC; uc003ziy.4; human.
DR   AGR; HGNC:6087; -.
DR   CTD; 3641; -.
DR   DisGeNET; 3641; -.
DR   GeneCards; INSL4; -.
DR   HGNC; HGNC:6087; INSL4.
DR   HPA; ENSG00000120211; Tissue enriched (placenta).
DR   MIM; 600910; gene.
DR   neXtProt; NX_Q14641; -.
DR   OpenTargets; ENSG00000120211; -.
DR   PharmGKB; PA29894; -.
DR   VEuPathDB; HostDB:ENSG00000120211; -.
DR   eggNOG; ENOG502TJQC; Eukaryota.
DR   GeneTree; ENSGT00940000154434; -.
DR   HOGENOM; CLU_1864514_0_0_1; -.
DR   InParanoid; Q14641; -.
DR   OMA; PSLFWSY; -.
DR   OrthoDB; 4688190at2759; -.
DR   PhylomeDB; Q14641; -.
DR   TreeFam; TF333404; -.
DR   PathwayCommons; Q14641; -.
DR   BioGRID-ORCS; 3641; 14 hits in 1139 CRISPR screens.
DR   GeneWiki; INSL4; -.
DR   GenomeRNAi; 3641; -.
DR   Pharos; Q14641; Tbio.
DR   PRO; PR:Q14641; -.
DR   Proteomes; UP000005640; Chromosome 9.
DR   RNAct; Q14641; Protein.
DR   Bgee; ENSG00000120211; Expressed in placenta and 16 other cell types or tissues.
DR   GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR   GO; GO:0005179; F:hormone activity; IEA:UniProtKB-KW.
DR   GO; GO:0005159; F:insulin-like growth factor receptor binding; TAS:ProtInc.
DR   GO; GO:0005102; F:signaling receptor binding; TAS:ProtInc.
DR   GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR   GO; GO:1901384; P:positive regulation of chorionic trophoblast cell proliferation; TAS:GO_Central.
DR   InterPro; IPR023258; Placentin.
DR   InterPro; IPR022421; Relaxin.
DR   PANTHER; PTHR12004:SF3; EARLY PLACENTA INSULIN-LIKE PEPTIDE; 1.
DR   PANTHER; PTHR12004; RELAXIN; 1.
DR   PRINTS; PR02033; PLACENTIN.
DR   PRINTS; PR02004; RELAXIN.
DR   PROSITE; PS00262; INSULIN; 1.
DR   Genevisible; Q14641; HS.
PE   1: Evidence at protein level;
KW   Cleavage on pair of basic residues; Direct protein sequencing;
KW   Disulfide bond; Hormone; Reference proteome; Secreted; Signal.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000269|PubMed:15340161"
FT   CHAIN           26..139
FT                   /note="Early placenta insulin-like peptide"
FT                   /id="PRO_0000016155"
FT   PEPTIDE         26..58
FT                   /note="Early placenta insulin-like peptide B chain"
FT                   /id="PRO_0000016156"
FT   PROPEP          59..114
FT                   /note="C peptide"
FT                   /id="PRO_0000016157"
FT   PEPTIDE         115..139
FT                   /note="Early placenta insulin-like peptide A chain"
FT                   /id="PRO_0000016158"
FT   DISULFID        31..125
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250"
FT   DISULFID        43..138
FT                   /note="Interchain (between B and A chains)"
FT                   /evidence="ECO:0000250"
FT   DISULFID        124..129
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   139 AA;  15445 MW;  47FB61F6F86C1342 CRC64;
     MASLFRSYLP AIWLLLSQLL RESLAAELRG CGPRFGKHLL SYCPMPEKTF TTTPGGWLLE
     SGRPKEMVST SNNKDGQALG TTSEFIPNLS PELKKPLSEG QPSLKKIILS RKKRSGRHRF
     DPFCCEVICD DGTSVKLCT
//