Alternative titles; symbols
HGNC Approved Gene Symbol: SPINT1
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38) : 15:40,844,048-40,858,207 (from NCBI)
The SPINT1 gene encodes an inhibitor of hepatocyte growth factor activator (HGFAC; 604552) and matriptase (606797) and is involved in degradation of the extracellular matrix (Oberst et al., 2001).
Shimomura et al. (1997) purified SPINT1, an inhibitor of HGFAC, from a conditioned medium of a stomach carcinoma cell line. They molecularly cloned the cDNA of SPINT1, which encodes a deduced 478-amino acid protein with a calculated molecular mass of 53.3 kD. The protein contains an N-terminal putative signal peptide sequence, a hydrophobic, membrane-associated C-terminal region, and a central region that encodes the processed, cleaved protein. SPINT1 has 3 potential N-glycosylation sites. Two regions show extensive similarity to the Kunitz-type sequence of serine protease inhibitors, but only one of these regions is believed to be responsible for the inhibitory activity of SPINT1. Between the 2 Kunitz domains is a region similar to the cysteine-rich ligand-binding domain of the low density lipoprotein receptor (LDLR; 606945). By Northern blot analysis, Shimomura et al. (1997) demonstrated that SPINT1 is expressed as a 2.5-kb transcript in various tissues, with high expression in adult placenta, kidney, pancreas, prostate, small intestine, fetal kidney, and fetal lung, and low expression in liver and adult lung.
Gross (2015) mapped the SPINT1 gene to chromosome 15q15.1 based on an alignment of the SPINT1 sequence (GenBank AB000095) with the genomic sequence (GRCh38).
Shimomura et al. (1997) showed that the inhibitory activity of SPINT1 is specific for HGF activator in the HGF (142409)-converting process. SPINT1 is produced as an active membrane-associated protein and is proteolytically cleaved and secreted.
Lin et al. (1999) purified the serine protease ST14 (606797) in a complex with SPINT1. By Northern and Western blot analysis of normal breast and breast cancer cell lines, Oberst et al. (2001) found complete concordance in expression of ST14 and SPINT1; the expression correlated with expression of epithelial cell markers.
Szabo et al. (2009) found that Spint -/- mice had severe growth retardation and did not survive beyond postnatal day 16. Spint1 -/- mice presented histologically with overt hyperkeratosis of the forestomach, hyperkeratosis and acanthosis of the epidermis, and hypotrichosis associated with abnormal cuticle development. Significant suppression of matriptase via a hypomorphic mutation in the St14 gene, to avoid lethality caused by complete loss of matriptase, reversed the phenotype of Spint1 -/- mice. Spint -/- St14 -/hypomorphic mice gained weight at near normal rates, had unaltered long-term survival, were outwardly healthy, and were histologically unremarkable. Spint -/- St14 -/hypomorphic mice were only distinguished from St14 -/hypomorphic mice by reduced accumulation of body fat.
Gross, M. B. Personal Communication. Baltimore, Md. 12/28/2015.
Lin, C.-Y., Anders, J., Johnson, M., Sang, Q. A., Dickson, R. B. Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity. J. Biol. Chem. 274: 18231-18236, 1999. [PubMed: 10373424] [Full Text: https://doi.org/10.1074/jbc.274.26.18231]
Oberst, M., Anders, J., Xie, B., Singh, B., Ossandon, M., Johnson, M., Dickson, R. B., Lin, C.-Y. Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Am. J. Path. 158: 1301-1311, 2001. [PubMed: 11290548] [Full Text: https://doi.org/10.1016/S0002-9440(10)64081-3]
Shimomura, T., Denda, K., Kitamura, A., Kawaguchi, T., Kito, M., Kondo, J., Kagaya, S., Qin, L., Takata, H., Miyazawa, K., Kitamura, N. Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine protease inhibitor. J. Biol. Chem. 272: 6370-6376, 1997. [PubMed: 9045658] [Full Text: https://doi.org/10.1074/jbc.272.10.6370]
Szabo, R., Kosa, P., List, K., Bugge, T. H. Loss of matriptase suppression underlies Spint1 mutation-associated ichthyosis and postnatal lethality. Am. J. Path. 174: 2015-2022, 2009. [PubMed: 19389929] [Full Text: https://doi.org/10.2353/ajpath.2009.090053]