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

Identity

HGNC
LOCATION
15q15.1
LOCUSID
ALIAS
HAI,HAI1,MANSC2
FUSION GENES

DNA/RNA

Atlas Image
Structure of the human SPINT1 gene.

Description

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.

Transcription

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.

Proteins

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.

Description

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.

Expression

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.

Localisation

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

Function

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
    Oncogenesis
    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.

    Bibliography

    Pubmed IDLast YearTitleAuthors

    Other Information

    Locus ID:

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

    Variants:

    dbSNP: 6692
    ClinVar: 6692
    TCGA: ENSG00000166145
    COSMIC: SPINT1

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000166145ENST00000344051O43278
    ENSG00000166145ENST00000562057O43278
    ENSG00000166145ENST00000563656H3BTQ8
    ENSG00000166145ENST00000564375H3BMB6
    ENSG00000166145ENST00000566928H3BR01
    ENSG00000166145ENST00000568580H3BVD9
    ENSG00000166145ENST00000568823H3BSM2
    ENSG00000166145ENST00000569589H3BNW5

    Expression (GTEx)

    0
    50
    100
    150
    200
    250
    300

    Pathways

    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
    Low
    Medium
    High

    References

    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

    Citation

    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