HAI-1 is an endogenous inhibitor of the kunitz-type serine proteinase HGF-activator (HGFA). HGF was first described as a hepatocyte-specific mitogen and survival factor, and has since been shown to exert a variety of actions on many cell types by binding to its MET receptor. HGF is activated by cleavage of the single-chain form to form a two-chain version by HGFA. HAI-1 also inhibits trypsin, and MTSP-1 (Matriptase), a serine proteinase that also activates HGF. HAI-1B is a splice variant of HAI-1, and contains a 16 amino acid insert after the first kringle domain, relative to the HAI-1 sequence. The longer sequence (HAI-1B) is 529 amino acids in length, with a predicted molecular weight of 58.4 kDa and a pI of 5.832. The shorter sequence, with 86% identity to HAI-1B, is 513 amino acids long, predicted weight of 56.9 kDa and a pI of 5.724. Message for each form is found in the same cells in roughly the same levels, but there does seem to be some differences in activity in the two forms. HAI-1 is more distantly related to HAI-2, which is found in 252 and 106 amino acid forms, predicting 35.4 and 10.9 kDa respectively, and more basic pIs of 8.09 and 8.639. The HAI proteins are glycosylated, and may have other post-translational modifications, thus the apparent molecular weight is 66 kDa for the full-length HAI-1. The HAI-1 antibodies do not recognize HAI-2. HAI-1 is down regulated in some tumor cells while MTSP-1 and HGFA levels are elevated, yielding increased net activity for these two HGF activators. In other cases, especially in tissues surrounding tumors, HAI-1 levels are thought to be elevated, perhaps in a protective stance. HAI-1 is secreted and membrane-inserted via a type-I transmembrane domain. The carboxyterminal end is a cytoplasmic domain, thought to interact with signaling and cytoskeletal machinery. The extracellular domains include a kringle domain (KD1) followed by an LDL receptor-like motif, another kringle domain (KD2), which is thought to be inactive or with much lower activity against HGF. HAI-1 is shed from the cell surface by cleavage extracellular to the transmembrane domain, yielding a 58 kDa form, and cleavage between the KD1 and the LDLR motif yields a 39-40 kDa form, which is thought to be more proteolytically active. A recommended starting concentration for Western blots is 1:1000 when using colorimetric substrates such as BCIP/NBT, and 1:5000 for chemiluminescent substrates. Higher concentrations of antibody may be needed for samples from more distantly related species.

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