Some other SPINK family members are similar in size, are encoded for by 4 exons and contain a single Kazal type serine protease inhibitor domain.

Maps to chromosomal region 5q32: 147,204,131-147,211,349 on reverse (minus) strand (7,219 bp). Gene consists of 4 exons (Horii et al., 1987). Region between 3.8 and 4.0 kb upstream from the translation initiation codon contains an interleukin-6 responsive element (IL6RE) and two potential AP-1 binding sites (Ohmachi et al., 1993; Yasuda et al., 1993). CAATCAATAAC sequence (-149 to -139) is a potential pancreas-specific regulatory element (Yasuda et al., 1998). This region in the SPINK1 promoter has been subsequently identified as a binding site for hepatic nuclear factor (HNF1) (Boulling et al., 2011). A putative binding site for pancreas-specific transcription factor 1 (PTF1) has also been identified within the SPINK1 promoter (Boulling et al., 2011).

SPINK1 mRNA (NCBI Reference Sequence: NM_003122.3) has 454 bp (Yamamoto et al., 1985). Expression, at least in some cell lines, is regulated by IL-6 (Yasuda et al., 1993). Three differentially spliced mRNA forms have been described (Ensembl, release 73). Two of these have been classified as protein encoding.

In the literature, SPINK1 is widely referred to as TATI (tumor-associated trypsin inhibitor) and PSTI (pancreatic secretory trypsin inhibitor).

SPINK1(NCBI Reference Sequence: NP_003113.2 ; UniProtKB/Swiss-Prot: ISK1_HUMAN, P00995; PDB: 1cgj; 1cgi; 1hpt) is a 6242 Da secreted protein, containing 79 amino acids. Mature SPINK1 contains 56 amino acids and three disulfide bonds. It has a Kazal-type serine protease inhibitor domain and belongs to the SPINK (serine peptidase inhibitor, Kazal-type) family. SPINK1 has been reported to inhibit several proteases, including human trypsin-1 and -2 (cationic and anionic trypsins), acrosin and granzyme A (Pubols et al., 1974; Huhtala et al., 1984; Turpeinen et al., 1988; Tsuzuki et al., 2003).

SPINK1 was first characterized in bovine pancreas (Kazal et al. 1948) and pancreatic juice (Greene 1966), and later from human pancreatic juice (Fritz et al 1967). SPINK1 is mainly expressed in the pancreas, but to a lesser extent also in several other tissues, e.g., in the gastrointestinal tract, including the liver, duodenum, small intestine, gall bladder, colon, appendix, stomach, and in the genitourinary tract, e.g., prostate and urothelium (Paju and Stenman, 2006; Itkonen and Stenman, 2014). Expression has been found also in kidney, lung, breast, brain, spleen and ovary. SPINK1 is often strongly expressed in ETS-rearrangement-negative prostate cancers (Tomlins et al., 2008). A putative bipartite pancreas-specific transcription factor 1 (PTF1)-binding sequence has been identified (Boulling et al., 2011) in the SPINK1 gene. Outside the pancreas, SPINK1 has been considered an inflammatory pleiotropic cytokine, which is regulated by immune and inflammatory responses. In some cell lines, the expression is regulated by IL-6 (Yasuda et al., 1993). In cultured prostate cancer cells, SPINK1 expression has been shown to be regulated by androgens (Paju et al., 2007). In mouse, the synthesis of Spink3 (mouse orthologue of SPINK1) is dependent upon testicular androgens in the sex accessory tissues, but not in the pancreas (Mills et al., 1987). Very high serum and urine concentrations occur in patients with pancreatitis (Ogawa, 1988). Serum levels of SPINK1 may also be elevated in several cancers, including prostate cancer, ovarian cancer and benign cysts, renal-cell carcinoma, bladder carcinoma, and colorectal cancer (Paju and Stenman, 2006; Itkonen and Stenman, 2014). Severe inflammation, tissue destruction and major trauma leads to an acute phase reaction causing increased circulating SPINK1 concentrations.

SPINK1 is highly expressed in the pancreas (Kazal et al., 1948). It has been localized to the zymogen granules of pancreatic acinar cells, where it protects the pancreas from premature activation of trypsinogens. SPINK1 is secreted into the pancreatic fluid along with digestive enzymes. Many cancers secrete SPINK1 causing elevated serum concentrations (Paju and Stenman, 2006; Itkonen and Stenman, 2014).

SPINK1 is a protease inhibitor and has been reported to inhibit human trypsin-1 and -2 (cationic and anionic trypsins), but not trypsin-3 (mesotrypsin)(Sahin-Tóth, 2005). SPINK1 also inhibits granzyme A (Tsuzuki et al., 2003), plasmin, urokinase, tissue plasminogen activator (Turpeinen et al., 1988) and acrosin (Huhtala et al., 1984). SPINK1 has been reported to exert growth stimulation of cultured cells (Niinobu et al., 1990) and to activate the EGF-receptor (Ozaki 2009; Ateeq et al., 2011). However, growth stimulation by mechanisms other than via EGF receptor cannot be ruled out. It has been suggested that SPINK1 mediates tumor growth, differentiation, and angiogenesis via stimulation of the EGF-receptor or by suppression of serine-protease- or caspase-dependent apoptosis (Ateeq et al., 2011; Gouyer et al., 2008). There is evidence that SPINK1 plays a role in tissue differentiation (Ohmuraya et al., 2005) and repair (Marchbank et al., 1996), reproduction (Huhtala, 1984) and regulation of apoptosis (Lu et al., 2011). Over-expression of SPINK1 in cancer could block cancer cell apoptosis resulting in suppression of the immune response and escape of cancer cells from immune surveillance (Lamontagne et al., 2010).

SPINK1 contains a Kazal-type serine protease inhibitor domain, found in many other proteins and especially in members of SPINK family. Apart from this domain, SPINKs do not share high sequence similarity. Apart from SPINK5, SPINKs are of similar size and most genes contain the same number of exons. Some of the family members lack functional annotatation. A functional SPINK1 orthologue, Spink3 (NP_033284.1), has been found in mouse. The rat has two orthologues, Spink1 (NP_690919.1) and Spink3 (NP_036806.1) (HomoloGene, Release 67). Orhologues have been found also in common chimpanzee (XP_001160275.1), rhesus macaque (XP_001102888.1), grey wolf (XP_850557.1) and cattle (NP_001020519.1). Sequence similarity between SPINK1 and EGF has been reported (Hunt et al., 1974).

NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP/) reports 631 SPINK1 SNPs (Homo sapiens, December 29., 2014). At least 15 missense mutations have been described in the mature polypeptide and three in the signal peptide (Chen and Férec, 2009). Association of mutations with familial pancreatitis and other diseases has been described (see below).