ID SPIT2_HUMAN Reviewed; 252 AA. AC O43291; A8K667; B4DLU1; O00271; O14895; Q5TZQ3; Q969E0; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 21-FEB-2001, sequence version 2. DT 13-FEB-2019, entry version 175. DE RecName: Full=Kunitz-type protease inhibitor 2; DE AltName: Full=Hepatocyte growth factor activator inhibitor type 2; DE Short=HAI-2; DE AltName: Full=Placental bikunin; DE Flags: Precursor; GN Name=SPINT2; Synonyms=HAI2, KOP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9346890; DOI=10.1074/jbc.272.44.27558; RA Kawaguchi T., Qin L., Shimomura T., Kondo J., Matsumoto K., Denda K., RA Kitamura N.; RT "Purification and cloning of hepatocyte growth factor activator RT inhibitor type 2, a Kunitz-type serine protease inhibitor."; RL J. Biol. Chem. 272:27558-27564(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 28-74. RC TISSUE=Placenta; RX PubMed=9115294; DOI=10.1074/jbc.272.18.12202; RA Marlor C.W., Delaria K.A., Davis G., Muller D.K., Greve J.M., RA Tamburini P.P.; RT "Identification and cloning of human placental bikunin, a novel serine RT protease inhibitor containing two Kunitz domains."; RL J. Biol. Chem. 272:12202-12208(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Pancreatic cancer; RX PubMed=9434156; RA Mueller-Pillasch F., Wallrapp C., Bartels K., Varga G., Friess H., RA Buechler M., Adler G., Gress T.M.; RT "Cloning of a new Kunitz-type protease inhibitor with a putative RT transmembrane domain overexpressed in pancreatic cancer."; RL Biochim. Biophys. Acta 1395:88-95(1998). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 MRNA] (ISOFORM 1). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor RT vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M., RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT RP LEU-200. RC TISSUE=Colon, and Ovary; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP PROTEIN SEQUENCE OF 28-42. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [10] RP VARIANT DIAR3 CYS-163, AND CHARACTERIZATION OF VARIANT DIAR3 CYS-163. RX PubMed=19185281; DOI=10.1016/j.ajhg.2009.01.004; RA Heinz-Erian P., Mueller T., Krabichler B., Schranz M., Becker C., RA Rueschendorf F., Nuernberg P., Rossier B., Vujic M., Booth I.W., RA Holmberg C., Wijmenga C., Grigelioniene G., Kneepkens C.M.F., RA Rosipal S., Mistrik M., Kappler M., Michaud L., Doczy L.-C., Siu V.M., RA Krantz M., Zoller H., Utermann G., Janecke A.R.; RT "Mutations in SPINT2 cause a syndromic form of congenital sodium RT diarrhea."; RL Am. J. Hum. Genet. 84:188-196(2009). CC -!- FUNCTION: Inhibitor of HGF activator. Also inhibits plasmin, CC plasma and tissue kallikrein, and factor XIa. CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I CC membrane protein {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O43291-1; Sequence=Displayed; CC Name=2; CC IsoId=O43291-2; Sequence=VSP_043680; CC Note=No experimental confirmation available.; CC -!- TISSUE SPECIFICITY: Expressed in placenta, kidney, pancreas, CC prostate, testis, thymus, and trachea. CC -!- DOMAIN: This inhibitor contains two inhibitory domains. CC -!- DISEASE: Diarrhea 3, secretory sodium, congenital, with or without CC other congenital anomalies (DIAR3) [MIM:270420]: A disease CC characterized by life-threatening secretory diarrhea, severe CC metabolic acidosis and hyponatremia. Hyponatremia is secondary to CC extraordinarily high fecal sodium loss, with low or normal CC excretion of urinary sodium, in the absence of infectious, CC autoimmune and endocrine causes. {ECO:0000269|PubMed:19185281}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. 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; AB006534; BAA25024.1; -; mRNA. DR EMBL; U78095; AAC02781.1; -; mRNA. DR EMBL; AF027205; AAB84031.1; -; mRNA. DR EMBL; AK291532; BAF84221.1; -; mRNA. DR EMBL; AK297154; BAG59653.1; -; mRNA. DR EMBL; BT020115; AAV38918.1; -; mRNA. DR EMBL; BT020116; AAV38919.1; -; mRNA. DR EMBL; BT020117; AAV38920.1; -; mRNA. DR EMBL; AC011479; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471126; EAW56766.1; -; Genomic_DNA. DR EMBL; CH471126; EAW56767.1; -; Genomic_DNA. DR EMBL; BC001668; AAH01668.1; -; mRNA. DR EMBL; BC007705; AAH07705.1; -; mRNA. DR EMBL; BC011951; AAH11951.1; -; mRNA. DR EMBL; BC011955; AAH11955.1; -; mRNA. DR EMBL; BC012868; AAH12868.1; -; mRNA. DR CCDS; CCDS12510.1; -. [O43291-1] DR CCDS; CCDS54261.1; -. [O43291-2] DR RefSeq; NP_001159575.1; NM_001166103.1. [O43291-2] DR RefSeq; NP_066925.1; NM_021102.3. [O43291-1] DR UniGene; Hs.31439; -. DR PDB; 4U32; X-ray; 1.65 A; X=34-88. DR PDBsum; 4U32; -. DR ProteinModelPortal; O43291; -. DR SMR; O43291; -. DR BioGrid; 115896; 109. DR IntAct; O43291; 1. DR MINT; O43291; -. DR STRING; 9606.ENSP00000301244; -. DR MEROPS; I02.009; -. DR iPTMnet; O43291; -. DR PhosphoSitePlus; O43291; -. DR BioMuta; SPINT2; -. DR EPD; O43291; -. DR jPOST; O43291; -. DR MaxQB; O43291; -. DR PaxDb; O43291; -. DR PeptideAtlas; O43291; -. DR PRIDE; O43291; -. DR ProteomicsDB; 48859; -. DR ProteomicsDB; 48860; -. [O43291-2] DR DNASU; 10653; -. DR Ensembl; ENST00000301244; ENSP00000301244; ENSG00000167642. [O43291-1] DR Ensembl; ENST00000454580; ENSP00000389788; ENSG00000167642. [O43291-2] DR GeneID; 10653; -. DR KEGG; hsa:10653; -. DR UCSC; uc002ohr.2; human. [O43291-1] DR CTD; 10653; -. DR DisGeNET; 10653; -. DR EuPathDB; HostDB:ENSG00000167642.12; -. DR GeneCards; SPINT2; -. DR HGNC; HGNC:11247; SPINT2. DR HPA; CAB018969; -. DR HPA; HPA011101; -. DR MalaCards; SPINT2; -. DR MIM; 270420; phenotype. DR MIM; 605124; gene. DR neXtProt; NX_O43291; -. DR OpenTargets; ENSG00000167642; -. DR Orphanet; 103908; Congenital sodium diarrhea. DR PharmGKB; PA36077; -. DR eggNOG; KOG4295; Eukaryota. DR eggNOG; ENOG410XQNP; LUCA. DR GeneTree; ENSGT00940000160348; -. DR HOGENOM; HOG000013109; -. DR HOVERGEN; HBG079207; -. DR InParanoid; O43291; -. DR OMA; CDNFIYG; -. DR OrthoDB; 1282068at2759; -. DR PhylomeDB; O43291; -. DR TreeFam; TF326553; -. DR Reactome; R-HSA-6806942; MET Receptor Activation. DR Reactome; R-HSA-8852405; Signaling by MST1. DR ChiTaRS; SPINT2; human. DR GeneWiki; SPINT2; -. DR GenomeRNAi; 10653; -. DR PRO; PR:O43291; -. DR Proteomes; UP000005640; Chromosome 19. DR Bgee; ENSG00000167642; Expressed in 225 organ(s), highest expression level in pituitary gland. DR ExpressionAtlas; O43291; baseline and differential. DR Genevisible; O43291; HS. DR GO; GO:0005737; C:cytoplasm; IDA:HGNC. DR GO; GO:0005576; C:extracellular region; TAS:ProtInc. DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl. DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB. DR GO; GO:0071711; P:basement membrane organization; IEA:Ensembl. DR GO; GO:0071773; P:cellular response to BMP stimulus; IEA:Ensembl. DR GO; GO:0060672; P:epithelial cell morphogenesis involved in placental branching; IEA:Ensembl. DR GO; GO:0007163; P:establishment or maintenance of cell polarity; IEA:Ensembl. DR GO; GO:2000146; P:negative regulation of cell motility; IDA:MGI. DR GO; GO:0022408; P:negative regulation of cell-cell adhesion; IDA:MGI. DR GO; GO:2000178; P:negative regulation of neural precursor cell proliferation; IEA:Ensembl. DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl. DR CDD; cd00109; KU; 2. DR Gene3D; 4.10.410.10; -; 2. DR InterPro; IPR002223; Kunitz_BPTI. DR InterPro; IPR036880; Kunitz_BPTI_sf. DR InterPro; IPR020901; Prtase_inh_Kunz-CS. DR Pfam; PF00014; Kunitz_BPTI; 2. DR PRINTS; PR00759; BASICPTASE. DR SMART; SM00131; KU; 2. DR SUPFAM; SSF57362; SSF57362; 2. DR PROSITE; PS00280; BPTI_KUNITZ_1; 2. DR PROSITE; PS50279; BPTI_KUNITZ_2; 2. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; KW Direct protein sequencing; Disease mutation; Disulfide bond; KW Glycoprotein; Membrane; Polymorphism; Protease inhibitor; KW Reference proteome; Repeat; Serine protease inhibitor; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1 27 {ECO:0000269|PubMed:15340161, FT ECO:0000269|PubMed:9115294}. FT CHAIN 28 252 Kunitz-type protease inhibitor 2. FT /FTId=PRO_0000016885. FT TOPO_DOM 28 197 Extracellular. {ECO:0000255}. FT TRANSMEM 198 218 Helical. {ECO:0000255}. FT TOPO_DOM 219 252 Cytoplasmic. {ECO:0000255}. FT DOMAIN 38 88 BPTI/Kunitz inhibitor 1. FT {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DOMAIN 133 183 BPTI/Kunitz inhibitor 2. FT {ECO:0000255|PROSITE-ProRule:PRU00031}. FT SITE 48 49 Reactive bond. {ECO:0000250}. FT SITE 143 144 Reactive bond. {ECO:0000250}. FT CARBOHYD 57 57 N-linked (GlcNAc...) asparagine. FT CARBOHYD 94 94 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 38 88 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DISULFID 47 71 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DISULFID 63 84 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DISULFID 133 183 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DISULFID 142 166 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT DISULFID 158 179 {ECO:0000255|PROSITE-ProRule:PRU00031}. FT VAR_SEQ 36 92 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_043680. FT VARIANT 163 163 Y -> C (in DIAR3; has a significantly FT reduced ability to inhibit trypsin FT compared to wild-type; FT dbSNP:rs121908403). FT {ECO:0000269|PubMed:19185281}. FT /FTId=VAR_058718. FT VARIANT 200 200 V -> L (in dbSNP:rs11548457). FT {ECO:0000269|PubMed:15489334}. FT /FTId=VAR_012482. FT CONFLICT 3 3 Q -> H (in Ref. 3; AAB84031). FT {ECO:0000305}. FT CONFLICT 11 11 R -> P (in Ref. 1; BAA25024). FT {ECO:0000305}. FT CONFLICT 53 53 R -> K (in Ref. 3; AAB84031). FT {ECO:0000305}. FT CONFLICT 240 240 D -> H (in Ref. 3; AAB84031). FT {ECO:0000305}. FT TURN 36 38 {ECO:0000244|PDB:4U32}. FT STRAND 51 57 {ECO:0000244|PDB:4U32}. FT TURN 58 61 {ECO:0000244|PDB:4U32}. FT STRAND 62 68 {ECO:0000244|PDB:4U32}. FT STRAND 70 72 {ECO:0000244|PDB:4U32}. FT STRAND 78 80 {ECO:0000244|PDB:4U32}. FT HELIX 81 87 {ECO:0000244|PDB:4U32}. SQ SEQUENCE 252 AA; 28228 MW; A7D3360C0EECAB2B CRC64; MAQLCGLRRS RAFLALLGSL LLSGVLAADR ERSIHDFCLV SKVVGRCRAS MPRWWYNVTD GSCQLFVYGG CDGNSNNYLT KEECLKKCAT VTENATGDLA TSRNAADSSV PSAPRRQDSE DHSSDMFNYE EYCTANAVTG PCRASFPRWY FDVERNSCNN FIYGGCRGNK NSYRSEEACM LRCFRQQENP PLPLGSKVVV LAGLFVMVLI LFLGASMVYL IRVARRNQER ALRTVWSSGD DKEQLVKNTY VL //