Furin at the cutting edge: From protein traffic to embryogenesis and disease

Abstract

Furin catalyses a simple biochemical reaction -the proteolytic maturation of proprotein substrates in the secretory pathway. But the simplicity of this reaction belies furin's broad and important roles in homeostasis, as well as in diseases ranging from Alzheimer's disease and cancer to anthrax and Ebola fever. This review summarizes various features of furin -its structural and enzymatic properties, intracellular localization, trafficking, substrates, and roles in vivo.Furin is a cellular ENDOPROTEASE that was identified in 1990 (BOX 1); it proteolytically activates large numbers of PROPROTEIN substrates in secretory pathway compartments. As well as activating pathogenic agents (BOX 2), furin has an essential role in embryogenesis, and catalyses the maturation of a strikingly diverse collection of proprotein substrates. These range from growth factors and receptors to extracellular-matrix proteins and even other protease systems that control disease. Until recently, furin was thought to be an unglamorous housekeeping protein; however, furin's crucial role in so many different cellular events -and in diseases ranging from from anthrax and bird flu (BOX 2) to cancer, dementia and Ebola fever -has caused researchers to re-evaluate it. In this review, I summarize the various features of furin: its structural and enzymatic properties, autoactivation, intracellular localization and trafficking; its substrates; and its roles in vivo, including the requirement for furin in determining the PATHOGENICITY of many viruses and bacteria.

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

“…Processing of membrane type-1 matrix metalloproteinase and anthrax-protective antigen-83 by proprotein convertase Proteolytic processing and activation of MT1-MMP by furin and related PCs occurs predominantly intracellularly (Thomas, 2002). In agreement, intracellularly expressed PDX significantly, albeit incompletely, inhibited the activation of MT1-MMP (Figures 4 and 5).…”

“…Furin-like PCs are involved in the processing of multiple cellular proteins including neuropeptides, peptide hormones, adhesion receptors, extracellular matrix proteins and growth factors, as well as many exogenous proteins of bacterial and viral origin (Thomas, 2002;Fugere and Day, 2005). Anthrax-protective antigen PA83 is a well-known target of furin (Seidah and Prat, 2002).…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Furin can also generate active TGF␤, which in turn increases furin expression (153). In fibroblastlike synoviocytes, TGF␤ increases ADAMTS-4 expression (154), such that a positive feedback loop is created, with increased levels of active ADAMTS-4 and aggrecanolysis (145). Conversely, we and other investigators have shown TGF␤ to block cartilage resorption (104,155,156).…”

“…PCs cleave numerous proteins including prohormones, serum proteins, bacterial toxins, viral glycoproteins, metalloproteinases, growth factors, growth factor receptors, neuropeptides, and adhesion molecules. Consequently, these enzymes are involved in numerous physiologic and pathologic pathways including embryonic development, Alzheimer's disease, cancer, obesity, diabetes, cardiovascular disease, and infectious disease (145,146).…”

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

“…35,36 Furin plays an important role in proteolytically activating large numbers of pro-protein substrates in the TGN compartment. 37 Hypoxia affects the transcription and cellular localization of furin, which might be one way of differentially controlling the activation of diverse signaling pathways. 22,38 TGF-b1 is mainly processed intracellularly, whereas other furin targets like bacterial toxins can also be efficiently cleaved in the extracellular compartment.…”