SPINK1

SPINK1, or serine protease inhibitor Kazal-type 1, is a gene that encodes a small secreted protein known as pancreatic secretory trypsin inhibitor (PSTI) or tumor-associated trypsin inhibitor (TATI). The SPINK1 gene is located on chromosome 5q32 and is expressed primarily in the pancreas, where the protein is secreted into pancreatic juice, but it is also detected in other tissues.

Functionally, SPINK1 inhibits trypsin and other serine proteases, acting as a safeguard against autodigestion from premature activation of trypsinogen in the pancreas. By binding to trypsin, it forms a stable complex that reduces proteolytic activity within the pancreatic acinar compartment.

Genetic variation in SPINK1 includes multiple variants described in relation to pancreatitis. The most studied is N34S, which is associated with an increased risk of chronic pancreatitis and may act as a disease modifier rather than a sole causative mutation. SPINK1 variants often contribute to disease in combination with other predisposition genes such as PRSS1 or CFTR, illustrating a polygenic component to pancreatitis susceptibility.

Clinical significance is broadening beyond pancreatitis. SPINK1 overexpression has been reported in several cancers, notably prostate cancer, where high SPINK1 expression defines a molecular subset and has been explored as a potential biomarker and therapeutic target. In addition, SPINK1 (TATI) has been studied as a serum biomarker in oncology and pancreatitis, although its clinical utility remains under investigation.

Structureally, the mature protein is a small secreted peptide of about 56 amino acids containing a Kazal-type serine protease inhibitor domain and is stabilized by disulfide bonds.