Curbing activation: proprotein convertases in homeostasis and pathology

Abstract

The proprotein convertases (PCs) are a seven-member family of endoproteases that activate proproteins by cleavage at basic motifs. Expression patterns for individual PCs vary widely, and all cells express several members. The list of substrates activated by PCs has grown to include neuropeptides, peptide hormones, growth and differentiation factors, receptors, enzymes, adhesion molecules, blood coagulation factors, plasma proteins, viral coat proteins, and bacterial toxins. It has become clear that the PC family plays a crucial role in a variety of physiological processes and is involved in the pathology of diseases such as cancer, viral infection, and Alzheimer's disease. Recent studies using PC inhibitors have demonstrated their potential as therapeutic targets. Despite the avalanche of in vitro data, the physiological role of individual PCs has remained largely elusive. Recently, however, knockout mouse models have been developed for furin, PC1, PC2, PC4, PC6B, LPC, and PACE4, and human patients with PC1 deficiency have been identified. The phenotypes range from undetectable to early embryonic lethality. The major lesson learned from these studies is that specific PC-substrate pairs do exist, but that there is substantial redundancy for the majority of substrates. To some extent, redundancy may be cell type and even species dependent.

Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model

“…22,25 Given the role of PCs in biological activation of inactive precursors, their inhibition could be an interesting clinical strategy against cancers by simultaneously disrupting the function of numerous proteins involved in tumor cell invasion and tumor progression. 15,20 However, the effect of ␣1-PDX on certain convertase substrates, like adhesion molecules, MMPs or other proteases, that could potentially contribute to tumorigenesis should be taken into account when considering PC inhibitors as therapeutic tools for a variety of diseases, including cancer. Thus, inhibition of cadherin cleavage results in decreased intercellular adhesive strength, 50 a situation observed in many tumors.…”

“…They are ubiquitously expressed and are involved in many physiological and pathological processes. 15 The potential clinical and pharmacological role of the convertases fostered the development of several inhibitors. The most promising protein-based specific inhibitor of PCs is an ␣1-antitrypsin variant known as ␣1-antitrypsin Portland (␣1-PDX).…”

“…␣1-PDX is a selective inhibitor of furin and, to a lesser extent, of PC5B 16 and blocks the convertase-dependent processing of various precursors, including integrins. 10,[17][18][19] Recent reports have suggested a possible role for PCs in tumorigenesis (for reviews, see references 15,20 ). Thus, furin expression levels correlate with invasiveness in human head and neck tumors and cell lines.…”

视网膜神经节细胞-5应激损伤后原蛋白转化酶-2和羧基肽酶-E介导的神经肽加工

“…They are expressed together or separately in functional cells in both vertebrates and invertebrates. The mammalian PCs have been demonstrated to involve in several diseases, such as HIV, hepatitis B, severe acute respiratory syndrome (SARS), anthrax, cancer, Alzheimer's disease, arthritis, stroke, glaucoma, and diabetes [5][6][7][8][9][10] .…”

Silencing of SPC2 Expression Using an Engineered δ Ribozyme in the Mouse βTC-3 Endocrine Cell Line

“…This hypothesis was supported by studies on SPC2-and SPC3-null mice where the processing of pro-insulin was severely impaired but not completely blocked (5,6). However, not all SPCs are amenable to null mouse models, because both SPC1-and SPC4-null mice are not viable (7).…”