Primary structure of a putative serine protease specific for IGF‐binding proteins

Zumbrunn, Jürg; Trüeb, Beat

doi:10.1016/s0014-5793(96)01229-x

Cited by 200 publications

(160 citation statements)

References 28 publications

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“…One possible explanation may lie within the fact that 2T3 cells are derived from transgenic mice overexpressing the simian virus 40 (SV40) T antigen and as such are immortalized [34]. The fact that HTRA1 gene expression is known to be significantly affected in SV40 transformed cells [35] would imply that modifications of the osteogenic status of these cells brought about by changes in HTRA1 expression and activity may not be truly representative of nonimmortalized, primary cells. Further studies aimed at determining the effects of HtrA1 gene silencing or exogenously added recombinant HTRA1 on primary mASC osteogenesis may help to clarify this point.…”

Section: Discussionmentioning

confidence: 99%

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

et al. 2012

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Mammalian high-temperature requirement serine protease A1 (HTRA1) is a secreted member of the trypsin family of serine proteases which can degrade a variety of bone matrix proteins and as such has been implicated in musculoskeletal development. In this study, we have investigated the role of HTRA1 in mesenchymal stem cell (MSC) osteogenesis and suggest a potential mechanism through which it controls matrix mineralization by differentiating boneforming cells. Osteogenic induction resulted in a significant elevation in the expression and secretion of HTRA1 in MSCs isolated from human bone marrow-derived MSCs (hBMSCs), mouse adipose-derived stromal cells (mASCs), and mouse embryonic stem cells. Recombinant HTRA1 enhanced the osteogenesis of hBMSCs as evidenced by significant changes in several osteogenic markers including integrin-binding sialoprotein (IBSP), bone morphogenetic protein 5 (BMP5), and sclerostin, and promoted matrix mineralization in differentiating boneforming osteoblasts. These stimulatory effects were not observed with proteolytically inactive HTRA1 and were abolished by small interfering RNA against HTRA1. Moreover, loss of HTRA1 function resulted in enhanced adipogenesis of hBMSCs. HTRA1 Immunofluorescence studies showed colocalization of HTRA1 with IBSP protein in osteogenic mASC spheroid cultures and was confirmed as being a newly identified HTRA1 substrate in cell cultures and in proteolytic enzyme assays. A role for HTRA1 in bone regeneration in vivo was also alluded to in bone fracture repair studies where HTRA1 was found localized predominantly to areas of new bone formation in association with IBSP. These data therefore implicate HTRA1 as having a central role in osteogenesis through modification of proteins within the extracellular matrix. STEM CELLS

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Section: Discussionmentioning

confidence: 99%

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

et al. 2012

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“…The RGD sequence noted by Johnson et al (1991) in the Salmonella typhimurium HtrA sequence is located within the second PDZ domain. A human protein, L56, present only in nontransformed cells, possesses a domain homologous to HtrA, preceded by an insulin-like growth factor-binding domain and a serpin domain (Zumbrunn and Trueb, 1996). A yeast hypothetical protein, N1897, consists of two tandem HtrA-like repeats, each complete with two PDZ domains (Ponting, 1997).…”

Section: Homologues In Other Organismsmentioning

confidence: 99%

The HtrA family of serine proteases

Pallen¹,

Wren²

1997

Molecular Microbiology

367

408

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SummaryHtrA, also known as DegP and probably identical to the Do protease, is a heat shock-induced serine protease that is active in the periplasm of Escherichia coli. Homologues of HtrA have been described in a wide range of bacteria and in eukaryotes. Its chief role is to degrade misfolded proteins in the periplasm. Substrate recognition probably involves the recently described PDZ domains in the C-terminal half of HtrA and, we suspect, has much in common with the substrate recognition system of the tail-specific protease, Prc (which also possesses a PDZ domain). The expression of htrA is regulated by a complex set of signal transduction pathways, which includes an alternative sigma factor, RpoE, an anti-sigma factor, RseA, a two-component regulatory system, CpxRA, and two phosphoprotein phosphatases, PrpA and PrpB. Mutations in the htrA genes of Salmonella, Brucella and Yersinia cause decreased survival in mice and/or macrophages, and htrA mutants can act as vaccines, as cloning hosts and as carriers of heterologous antigens.

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“…HtrAs are chaperones that are essential for bacterial survival after heat shock or oxidative stress (6,23,34,43). In addition to Omi, the family of eukaryotic HtrAs includes two other members: HtrA1/L56 (18,59) and HtrA3/PRSP (31). Both HtrA1 and HtrA3 are secreted proteins whose normal function is not known.…”

mentioning

confidence: 99%

Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells

Cilenti¹,

Kyriazis²,

Soundarapandian³

et al. 2005

American Journal of Physiology-Renal Physiology

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Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.

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Primary structure of a putative serine protease specific for IGF‐binding proteins

Cited by 200 publications

References 28 publications

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

Human Serine Protease HTRA1 Positively Regulates Osteogenesis of Human Bone Marrow-derived Mesenchymal Stem Cells and Mineralization of Differentiating Bone-forming Cells Through the Modulation of Extracellular Matrix Protein

The HtrA family of serine proteases

Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells

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