[Frontiers in Bioscience 14, 2911-2922, January 1, 2009]

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

Chunsik Lee1, Erik Bongcam-Rudloff2, Christian Sollner3, Willi Jahnen-Dechent4, Lena Claesson-Welsh1

1Department of Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden, 2Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 24 Uppsala, Sweden, 3Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge CB10 1HH, United Kingdom, 4Department of Biomedical Engineering, RWTH Aachen University Hospital, 52074 Aachen, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Nomenclature
4. Chromosomal localization and gene organization
5. Structure of type 3 cystatins
6. Production, distribution, and plasma concentration of type 3 cystatins
7. Physiological roles of type 3 cystatins 7.1. Regulation of mineralization by AHSG
7.2. AHSG and FETUB in regulation of tumor growth
7.3. Antibacterial function of KNG and HRG
7.4. Regulation of coagulation and platelet function by KNG and HRG
7.5. KNG and HRG in regulation of angiogenesis 8. Conclusions
9. Acknowledgements 10. References

1. ABSTRACT

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.