Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family

Abstract

The inhibitory mechanism against proteases is important in the maintenance of homeostasis or health in the body. The human ovalbumin serpin (ov-serpin)/clade B serpin family is one group of the human serpins, a family of serine protease inhibitors. They have acquired diversity in the profiles of target proteases, inhibitory mechanisms, and localization patterns during their evolution. Most serpins target serine proteases, however, some ov-serpins target only cysteine proteases or both serine and cysteine proteases and furthermore, several ov-serpins do not possess inhibitory activities. Although the ov-serpins act primarily as intracellular serpins, some show extracellular and nuclear localizations. Such diversity enables the ov-serpins to play multiple physiological roles in the body. Recent analyses have revealed that the functions of human ov-serpins are more diversified than we previously knew. In this article, we describe recent progress in our understanding of how the human ov-serpin/clade B serpin family demonstrates diversity.

TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2

“…These complexes were suggested to contain a serine protease that is activated during this process, but this activity was never identified. Nevertheless, these observations raise the hypothesis that some ov-serpins may share a common function in controlling cell death, and that their specific physiological roles may have been obscured as a result of redundancy (14,41). Although it remains to be further investigated, our observations that PAI-2 and TG2 interact in cells, and mediate a common antiapoptotic response, suggest that these unconventional antiapoptotic factors participate in a posttranslational mechanism that controls caspase-3 activation.…”

“…Although it remains to be determined whether TG2 can also crosslink other caspases, including caspase-8, this observation provides a missing molecular link that explains the observation made more than a decade ago that the C-D interhelical domain or C-D loop of PAI-2, a conserved protein binding domain among ovserpin family members (14), was essential for the antiapoptotic function of PAI-2 in TNF-stimulated cells (22). It was postulated that an interaction between the C-D loop and unknown proteins was likely to be important for resistance to apoptosis.…”

“…Defective expression of such genes may account, at least in part, for TNF-induced liver failure in Tbk1 −/− embryos. We now show that TBK1 controls the expression of plasminogen activator inhibitor-2 (PAI-2), a member of the ov-serpin family (14). PAI-2 maintains survival of TNF-stimulated cells through the protein modifier transglutaminase 2 (TG2), a pleiotropic enzyme able to cross-link procaspase-3 into inactive dimers.…”

Expression of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor and maspin in oral squamous cell carcinoma: Association with mode of invasion and clinicopathological factors

“…Several proteolytic enzyme systems, including plasminogen activators, matrix metalloproteinases (MMPs) and other enzymes, are considered to be intimately involved in the invasion and metastasis of tumor cells (1,2). The serine protease urokinase-type of plasminogen activator (uPA) together with the uPA receptor (uPAR), which plays an essential role in the conversion of plasminogen to active plasmin, have been implicated in facilitating pericellular proteolysis and oncogenic signal transduction in cancer cells (3,4). The proteolytic activity of uPAR-associated uPA is blocked by serine protease inhibitors such as maspin and PAI-1,2 (plasminogen activator inhibitor-1), leading to internalization of the trimeric complex, degradation of uPA and recycling of uPAR (5)(6)(7)(8)(9) Invasion and metastasis are the most crucial characteristics of malignant tumors.…”

Role of squamous cell carcinoma antigen-1 on liver cells after partial hepatectomy in transgenic mice

“…Genomic cloning and sequencing revealed that they are 91% identical at the amino acid level, but show distinct properties and substrates (5) and their physiological roles are poorly understood.…”