Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein

This review describes the properties of four structurally related, abundant plasma proteins denoted fetuin-A/alpha-2-Heremans Schmid-glycoprotein (AHSG), fetuin-B (FETUB), kininogen (KNG) and histidine-rich glycoprotein (HRG). These proteins form a subgroup (denoted type 3) within the cystatin superfamily of cysteine protease inhibitors. Apart from KNG, the type 3 proteins appear to lack cystatin activity. AHSG has its major function in regulation of bone mineralization; the physiological role of FETUB is poorly understood. KNG serves dual functions in the assembly of the protein complex initiating the surface-activated blood coagulation cascade and as a precursor for the kinin hormones. The heparin-binding HRG has also been implicated in regulation of coagulation. In addition, several members of the type 3 cystatins have been implicated in tumor growth and shown to regulate endothelial cell function and formation of new blood vessels, angiogenesis. Thus, these proteins may potentially be useful in treatment of diseases characterized by excess angiogenesis such as cancer.