SPINT1 (serine peptidase inhibitor, Kunitz type 1)

2009-02-01   Hiroaki Kataoka 

Section of Oncopathology, Regenerative Biology, Faculty of Medicine, University of Miyazaki 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan




Atlas Image
Structure of the human SPINT1 gene.


The human SPINT1 gene spans approximately 13.6 kb in length and consists of 11 exons separated by 10 introns. The size of the exons ranges from 26 bp (exon 6) to about 0.8kb (exon 11). The size of introns ranges from 83 bp to about 7 kb. The first exon encodes only a part of 5-untranslated region (UTR) of the SPINT1 transcript. Exon 2 contains the remaining 5-UTR and the putative signal sequence. Two Kunitz-type inhibitor domains (KD-1 and KD-2) are encoded by exons 5 and 9, respectively.


There are two major transcripts, isoform 1 (also known as HAI-1B) and isoform 2 (also known as HAI-1 or HAI-1A) produced by alternative splicing. Isoform 1 and isoform 2 mRNAs encode for 529 and 513 amino acids, respectively.


Atlas Image
Structures of SPINT1 protein isoform 1 (HAI-1B) and isoform 2 (HAI-1A). SP, signal peptide; MANSC, motif at N terminus with seven cysteines; KD-1, Kunitz domain-1; LDLa, low-density lipoprotein receptor domain class A; KD-2, Kunitz domain-2; TM, transmembrane domain. Isoform 1 (HAI-1B) contains an extra 16 amino acids adjacent to the C terminus of KD-1.


The protein encoded by this gene is a member of the Kunitz family of serine proteinase inhibitors. Shimomura et al. (1997) purified this protein from a conditioned medium of a gastric carcinoma cell line MKN45 as a potent inhibitor specific for hepatocyte growth factor activator (HGFAC), a serum serine proteinase that is thought to be involved in the proteolytic activation of hepatocyte growth factor (HGF) in injured tissues. For this reason, SPINT1 was initially designated as HGFAC inhibitor type 1 (HAI-1). The initially cloned cDNA of SPINT1 encoded a 513 amino acids protein (478-amino acid mature protein with a calculated molecular mass of 53.3 kD). SPINT1 is a transmembrane protein expressed on the cell surface. It is composed of an extracellular domain containing an N-terminal Kunitz domain (KD1), a low-density lipoprotein (LDL) receptor-like domain and a C-terminal Kunitz domain (KD2), followed by a transmembrane region and a short cytoplasmic domain. Later, a major transcript variant, also known as HAI-1B, was reported by Kirchhofer et al. (2003). This variant encodes the longer isoform consisting of an extra 16 amino acids adjacent to the C terminus of Kunitz domain-1 (KD1); however, there is no functional difference between HAI-1 (HAI-1A) and HAI-1B.
Previous studies demonstrated that SPINT1 potently inhibits the action of a variety of trypsin-like serine proteinases, some of which may be involved in carcinogenesis, invasion and metastasis. These proteinases include HGFAC, matriptase/ST14, hepsin/TMPRSS1 and human kallikrein 1-related peptidases such as KLK4 and KLK5. Among them, matriptase/ST14 and hepsin/TMPRSS1 belong to the type II transmembrane serine protease superfamily. Other possible target proteinases include prostasin/PRSS8 and trypsin. Evidence suggests that matriptase/ST14 is the most important cognate proteinase of SPINT1 on epithelial surface. KD-1 is responsible for the inhibition of two major target proteinases, matriptase/ST14 and HGFAC.


SPINT1 protein is strongly expressed in the surface epithelium of gastrointestinal tracts, endocervical epithelium, ductal epithelia of biliary tracts and pancreas, prostatic glandular epithelium and renal tubular epithelium. It is also strongly expressed in hair cortex and cuticle cells, and to a lesser degree in epidermal keratinocytes. Mesothelial cells on the serous surface also express SPINT1. Weaker expression has been detected in the endothelial cells of capillaries, venules and lymphatics. Placental tissue shows very high level of SPINT1 mRNA, and villous cytotrophoblasts are mainly responsible for this expression.


SPINT1 is mainly located on the basolateral membrane of polarized epithelial cells.


To date, several proposed functions of SPINT1 have been reported.
  • Inhibition of serine proteinases: SPINT1 strongly inhibits HGFAC, trypsin, KLK4, KLK5, matriptase/ST14, prostasin/PRSS8 and hepsin/TMPRSS1.
  • Optimal regulation of pericellular proteinase activity: Evidence has suggested that SPINT1 is required for the trafficking of proforms of matriptase/ST14 to the cell surface and also for the activation of pro-matriptase/ST14 even though it can inhibit matriptase/ST14 activity. Therefore, without SPINT1, activation and proper localization of matriptase/ST14 appear to be significantly impaired. Such paradoxical effects of SPINT1 are also observed in the interaction with HGFAC. SPINT1 inhibits HGFAC, but paradoxically, serves as a reservoir of active HGFAC on the cell surface.
  • Regulation of pericellular HGF activation: Among target proteinases of SPINT1, HGFAC, matriptase/ST14 and hepsin/TMPRSS1 are known to activate precursor form of HGF (proHGF). Thus, SPINT1 is thought to regulate pericellular proHGF activation.
  • Function in the placenta development: SPINT1 is essential in the placental development, as SPINT1-deficient mouse embryos die during mid-gestation due to impaired formation of the placental labyrinth layer.
  • Function in the skin development: Rescue of the placental function results in successful delivery of SPINT-1-deficient neonates. However, they die within 16 days after delivery with significant skin abnormalities such as abnormal keratinization and impaired formation of hair cuticle. Therefore, SPINT1 is critical in the regulated keratinization of epidermis and formation of hair cuticle.
  • Tumor suppressor activity: Transgenic overexpression of matriptase/ST14 resulted in skin carcinogenesis. However, the development of skin cancer (squamous cell carcinoma) was suppressed when SPINT1 was co-expressed.
  • Homology

    SPINT-2 (also known as HAI-2 or placental bikunin) is also a membrane-bound Kunitz-type serine proteinase inhibitor consisting of two extracellular Kunitz domain. The amino acids identity between SPINT1 KD-1 and SPINT2 KD-1 is 54%, and between SPINT1 KD-2 and SPINT2 KD-2 is 36 %. However, SPINT2 lacks MANSC domain and LDL receptor-like domain.

    Implicated in

    Entity name
    Various cancers
    A possible tumor suppressor activity of SPINT1 has been reported in matriptase/ST14-induced skin carcinogenesis. Immunohistochemical studies suggest that the balance between SPINT1 and its target proteinase such as matriptase/ST14 may be important in the progression of breast cancer and prostate cancer. Downregulation of SPINT1 is also reported in part of the colon, renal cell and ovarian carcinoma cases. In vitro knockdown of SPINT1 results in an invasive phenotype of certain epithelial and carcinoma cells.


    Pubmed IDLast YearTitleAuthors
    118051182002Functional characterization of Kunitz domains in hepatocyte growth factor activator inhibitor type 1.Denda K et al
    171749462007Hepatocyte growth factor activator inhibitor-1 (HAI-1) is essential for the integrity of basement membranes in the developing placental labyrinth.Fan B et al
    161031262005Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin.Fan B et al
    184025522008Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary.Godiksen S et al
    151246312004MANSC: a seven-cysteine-containing domain present in animal membrane and extracellular proteins.Guo J et al
    107626182000Upregulation of HGF activator inhibitor type 1 but not type 2 along with regeneration of intestinal mucosa.Itoh H et al
    108241232000Genomic structure and chromosomal localization of the human hepatocyte growth factor activator inhibitor type 1 and 2 genes.Itoh H et al
    126157282003Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer.Kang JY et al
    127849982003Roles of hepatocyte growth factor (HGF) activator and HGF activator inhibitor in the pericellular activation of HGF/scatter factor.Kataoka H et al
    110132442000Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment.Kataoka H et al
    157928012005Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2.Kirchhofer D et al
    180483492008Roles of functional and structural domains of hepatocyte growth factor activator inhibitor type 1 in the inhibition of matriptase.Kojima K et al
    187699352008Expression of hepatocyte growth factor activator inhibitor type 1 on the epithelial cell surface is regulated by hypoxic and oxidative stresses.Komaki W et al
    155908952005Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells.Lee MS et al
    103734251999Purification and characterization of a complex containing matriptase and a Kunitz-type serine protease inhibitor from human milk.Lin CY et al
    161032202005Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation.List K et al
    178814992007Live imaging of chronic inflammation caused by mutation of zebrafish Hai1.Mathias JR et al
    188325872008Defect of hepatocyte growth factor activator inhibitor type 1/serine protease inhibitor, Kunitz type 1 (Hai-1/Spint1) leads to ichthyosis-like condition and abnormal hair development in mice.Nagaike K et al
    163532472006Serum hepatocyte growth factor activator inhibitor type I (HAI-I) and type 2 (HAI-2) in prostate cancer.Nagakawa O et al
    191484682009Expression of hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2) in ovarian cancer.Nakamura K et al
    112905482001Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo.Oberst M et al
    158000532005HAI-1 regulates activation and expression of matriptase, a membrane-bound serine protease.Oberst MD et al
    119481202002Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters.Oberst MD et al
    127387782003The activation of matriptase requires its noncatalytic domains, serine protease domain, and its cognate inhibitor.Oberst MD et al
    165575972006Hepatocyte growth factor activation inhibitors (HAI-1 and HAI-2) regulate HGF-induced invasion of human breast cancer cells.Parr C et al
    147344712004The hepatocyte growth factor regulatory factors in human breast cancer.Parr C et al
    164929082006A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1.Saleem M et al
    177862952007Suppression of hepatocyte growth factor activator inhibitor-1 leads to a more aggressive phenotype of prostate cancer cells in vitro.Sanders AJ et al
    90456581997Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor.Shimomura T et al
    169833412007Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development.Szabo R et al
    159648232005Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for branching morphogenesis in the chorioallantoic placenta.Tanaka H et al
    147138482004Hepatocyte growth factor activator inhibitor types 1 and 2 are expressed by tubular epithelium in kidney and down-regulated in renal cell carcinoma.Yamauchi M et al

    Other Information

    Locus ID:

    NCBI: 6692
    MIM: 605123
    HGNC: 11246
    Ensembl: ENSG00000166145


    dbSNP: 6692
    ClinVar: 6692
    TCGA: ENSG00000166145


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Transcriptional misregulation in cancerKEGGko05202
    Transcriptional misregulation in cancerKEGGhsa05202
    Signal TransductionREACTOMER-HSA-162582
    Signaling by MST1REACTOMER-HSA-8852405
    Signaling by METREACTOMER-HSA-6806834
    MET Receptor ActivationREACTOMER-HSA-6806942

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    173894012007Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway.54
    187137502008Potent inhibition and global co-localization implicate the transmembrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity.47
    195355142009Polarized epithelial cells secrete matriptase as a consequence of zymogen activation and HAI-1-mediated inhibition.38
    128150392003Tissue expression, protease specificity, and Kunitz domain functions of hepatocyte growth factor activator inhibitor-1B (HAI-1B), a new splice variant of HAI-1.34
    161031262005Identification of hepatocyte growth factor activator inhibitor-1B as a potential physiological inhibitor of prostasin.33
    168200462006The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals.32
    179815752008Zymogen activation, inhibition, and ectodomain shedding of matriptase.32
    192235332009Hepatocyte growth factor activator inhibitor type 1 regulates epithelial to mesenchymal transition through membrane-bound serine proteinases.32
    206967672010Regulation of the matriptase-prostasin cell surface proteolytic cascade by hepatocyte growth factor activator inhibitor-1 during epidermal differentiation.29
    110132442000Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator (HGFA) and regulates HGFA activity in the pericellular microenvironment.24


    Hiroaki Kataoka

    SPINT1 (serine peptidase inhibitor, Kunitz type 1)

    Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

    Online version: http://atlasgeneticsoncology.org/gene/44384/spint1