HGF is synthesized and secreted as an inactive single chain precursor (pro-HGF) that is stored in the extracellular matrix because of its high affinity for proteoglycans, and further processing by serine proteases into the two-chain form is coupled to its activation. In the extracellular environment, pro-HGF undergoes proteolytic cleavage at residues Arg494–Val495 to give rise to the biologically active form, a disulfide-linkedα/β heterodimer . The α-chain consists of an N-terminal domain followed by four kringle domains; the β-chain shares structural homology with the chymotrypsin family of serine proteases but lacks proteolytic activity.
Pro-HGF is proteolytically activated in response to tissue injury. Strikingly, the enzymatic activity leading to pro-HGF conversion into HGF is triggered only in the injured tissues. Thus, the proteolytic activation system functions in vivo as a regulatory mechanism for targeting HGF actions to injured tissues. Several proteases are involved in the activation of pro-HGF, such as HGF activator (HGFA), urokinase-type plasminogen activator (uPA), plasma kallikrein, coagulation factors XI (FXI) and XII (FXII), TMPRSS13 (transmembrane protease serine S1 member 13, a type II transmembrane serine protease), matriptase, and hepsin.
HGFA is the most powerful activator to pro-HGF. The activation process of HGFA is a complex and cascade event. Before activating, HGFA exist as a form of Pro-HGF. Organ injuries, tissue injuries and other conditions can cause blood clotting will activate pro-thrombin. Activated thrombin acts as a potent activator to the inactive HGF activator (pro-HGFA). After being activated, HGFA acts as one of the most powerful to pro-HGF binding to the cleavage site, Arg 494-Val 495, between α and β subunit. Undergoing proteolytic cleavage, pro-HGF gives rise to the biologically active form, a disulfide-linked α/β heterodimer. The process can be seen in figure 1.
figure1: HGFA Activation Process (Photocredit:W.G. Jiang et al. 2005)