The two main factors responsible for HGF activation are HGFA and matriptase. HGFA and matriptase action is regulated by two novel Kunitztype serine protease inhibitors termed hepatocyte growth factor activator inhibitor type 1 (HAI-1) and hepatocyte growth factor activator inhibitor type 2 (HAI-2). However, the roles of HAI-1 and HAI-2 in the body are still unclear; these inhibitors may play multiple roles in the body, and have been linked to a variety of physiological processes. Very little is
known about the regulation of HGF activity, and the interaction between the HGF activators (HGFA and matriptase) and the HGF activation inhibitors (HAI-1 and HAI-2).
4.2.1 Discovery of the HAI's
HGFA is found as an inactive precursor in human plasma, however, in human serum HGFA is detected in its active form. This suggested that a factor responsible for inhibiting HGFA action would not be present in the serum. Therefore, it seemed reasonable to assume that an inhibitor to HGFA may be produced by the tissues. Shimomura et al. (91), decided to examine human cell lines for an inhibitory factor against HGFA action. This group identified an inhibitory protein in the conditioned media of a variety of cell lines. The protein was then purified from a human MKN45 stomach carcinoma cell line and cloned to reveal a novel Kunitz-type serine protease inhibitor. The newly discovered HGFA inhibitor was designated HGF activator inhibitor (HAI). However, soon after the discovery of HAI, a second inhibitor of HGFA action was identified from the conditioned media of the same stomach carcinoma cell line (92). This newly discovered HGFA inhibitor was purified, cloned, and found to be another new Kunitz-type serine protease inhibitor. To distinguish between these two very similar HGFA inhibitors, they were designated HAI-1 and HAI-2.
4.2.2 Structure and function of HAI's
HAI-1 and HAI-2 are a unique class of serine protease inhibitors as they are synthesised as transmembrane glycoproteins rather than secreted forms. They are type 1 transmembrane proteins, and have two Kunitztype serine protease domains, the first of which is thought to be responsible for the HGFA-inhibitory action (122). Presently the target protease/s for the second Kunitz domain is unknown. HAI-1 and HAI-2 are synthe-sised on the cell surface and appear to be secreted by ectodomain shedding through proteolytic cleavage at the juxtamembrane part of the protein, this release of the inhibitors could decide the function of HAI-1 and HAI-2.
HAIs have emerged to play roles in mediating a diverse range of cellular functions through their ability to control the biological activation of proteins. HAI-1 is now reported to inhibit the action of HGFA, matriptase, hepsin, plasmin, and trypsin; whereas, HAI-2 inhibits HGFA, hepsin, trypsin, plasmin, tissue kallikreins, and factor XIa activity.
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