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American Journal of Physiology. Lung... May 2017More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary,... (Review)
Review
More than 2% of all human genes are coding for a complex system of more than 700 proteases and protease inhibitors. Among them, serine proteases play extraordinary, diverse functions in different physiological and pathological processes. The human airway trypsin-like protease (HAT), also referred to as TMPRSS11D and serine 11D, belongs to the emerging family of cell surface proteolytic enzymes, the type II transmembrane serine proteases (TTSPs). Through the cleavage of its four major identified substrates, HAT triggers specific responses, notably in epithelial cells, within the pericellular and extracellular environment, including notably inflammatory cytokine production, inflammatory cell recruitment, or anticoagulant processes. This review summarizes the potential role of this recently described protease in mediating cell surface proteolytic events, to highlight the structural features, proteolytic activity, and regulation, including the expression profile of HAT, and discuss its possible roles in respiratory physiology and disease.
Topics: Animals; Biocatalysis; Fetal Development; Humans; Models, Biological; Respiration Disorders; Serine Endopeptidases
PubMed: 28235951
DOI: 10.1152/ajplung.00509.2016 -
Experimental & Molecular Medicine Apr 2023Proteases are involved in almost all biological processes, implying their importance for both health and pathological conditions. Dysregulation of proteases is a key... (Review)
Review
Proteases are involved in almost all biological processes, implying their importance for both health and pathological conditions. Dysregulation of proteases is a key event in cancer. Initially, research identified their role in invasion and metastasis, but more recent studies have shown that proteases are involved in all stages of cancer development and progression, both directly through proteolytic activity and indirectly via regulation of cellular signaling and functions. Over the past two decades, a novel subfamily of serine proteases called type II transmembrane serine proteases (TTSPs) has been identified. Many TTSPs are overexpressed by a variety of tumors and are potential novel markers of tumor development and progression; these TTSPs are possible molecular targets for anticancer therapeutics. The transmembrane protease serine 4 (TMPRSS4), a member of the TTSP family, is upregulated in pancreatic, colorectal, gastric, lung, thyroid, prostate, and several other cancers; indeed, elevated expression of TMPRSS4 often correlates with poor prognosis. Based on its broad expression profile in cancer, TMPRSS4 has been the focus of attention in anticancer research. This review summarizes up-to-date information regarding the expression, regulation, and clinical relevance of TMPRSS4, as well as its role in pathological contexts, particularly in cancer. It also provides a general overview of epithelial-mesenchymal transition and TTSPs.
Topics: Male; Humans; Serine Proteases; Neoplasms; Lung; Membrane Proteins; Serine Endopeptidases
PubMed: 37009799
DOI: 10.1038/s12276-023-00975-5 -
The FEBS Journal May 2017Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix (ECM)... (Review)
Review
Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix (ECM) protein-degrading enzymes which allowed cancer cells to breach the basement membrane and invade surrounding tissue. However, recently, there has been a shift in the view of cell surface proteases, including serine proteases, as proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. Of the 176 human serine proteases currently identified, a subset of 17, known as type II transmembrane serine proteases (TTSPs). Many have been shown to be relevant to cancer progression since they were first identified as a family around the turn of the century. To this end, altered expression of TTSPs appeared as a trademark of several tumor types. However, the substrates and underlying signaling pathways remained unclear. Localization of these proteins to the cell surface places them in the unique position to mediate signal transduction between the cell and its surrounding environment. Many of the TTSPs have already been shown to play key roles in processes such as postnatal development, tissue homeostasis, and tumor progression, which share overlapping molecular mechanisms. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling.
Topics: Animals; Humans; Membrane Proteins; Neoplasms; Serine Endopeptidases; Serine Proteases; Signal Transduction
PubMed: 27870503
DOI: 10.1111/febs.13971 -
Frontiers in Immunology 2022Serine proteases has been considered to be closely associated with the inflammatory response and tumor progression. As a novel serine protease, the biological function...
Serine proteases has been considered to be closely associated with the inflammatory response and tumor progression. As a novel serine protease, the biological function of PRSS23 is rarely studied in cancers. In this study, the prognostic significance of PRSS23 was analyzed in two-independent gastric cancer (GC) cohorts. PRSS23 overexpression was clinically correlated with poor prognosis and macrophage infiltration of GC patients. Loss-of-function study verified that PRSS23 plays oncogenic role in GC. RNA-seq, qRT-PCR, western blotting and ELISA assay confirmed that serine protease PRSS23 positively regulated FGF2 expression and secretion. Single-cell analysis and gene expression correlation analysis showed that PRSS23 and FGF2 were high expressed in fibroblasts, and highly co-expressed with the biomarkers of tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and mesenchymal cells. Functional analysis confirmed PRSS23/FGF2 was required for TAM infiltration. Rescue assay further verified that PRSS23 promotes GC progression and TAM infiltration through FGF2. Survival analysis showed that high infiltration of M1-macrophage predicted favorable prognosis, while high infiltration level of M2-macrophage predicted poor prognosis in GC. Our finding highlights that PRSS23 promotes TAM infiltration through regulating FGF2 expression and secretion, thereby resulting in a poor prognosis.
Topics: Biomarkers; Fibroblast Growth Factor 2; Humans; Serine Endopeptidases; Serine Proteases; Stomach Neoplasms; Tumor-Associated Macrophages
PubMed: 36189305
DOI: 10.3389/fimmu.2022.955841 -
Immunobiology Aug 1998Mannose-binding lectin (MBL) is a serum component which participates in innate immunity by activating complement via a novel pathway. Human MBL forms complexes with two... (Comparative Study)
Comparative Study Review
Mannose-binding lectin (MBL) is a serum component which participates in innate immunity by activating complement via a novel pathway. Human MBL forms complexes with two types of serine proteases termed MASP (MBL-associated serine protease). These two proteases, MASP1 and MASP2, are structurally similar to one another as well as to C1r and C1s. Together, MASP, C1r and C1s constitute a novel serine protease family. It is likely that human MASP1 is able to activate C3, while human MASP2 cleaves C4, although further functional studies are required to confirm this. Based on the analysis of MASP cDNA of vertebrates and ascidians, the MASP/C1r/C1s family can be classified into two groups. The first group is characterized by a histidine loop in its serine protease domain, an active-center serine encoded by TCN, and a proline as the amino acid residue at the-3 position from the active serine. Human MASP1, mouse MASP1, Xenopus MASP1 and ascidian MASPs all belong to this group. MASP of the second group has structural features which are distinct from those of the first group: an absence of a histidine loop, an active-serine encoded by AGY, and an alanine or valine as the amino acid residue at the -3 position from the active-serine. The second group includes human MASP2, Xenopus MASP2, carp MASP, shark MASP, C1r and C1s. The TCN-type of MASP may have emerged prior to the AGY-type as an ancestral protease of the MASP/C1r/C1s family and played a crucial role in cleaving C3.
Topics: Animals; Binding Sites; Carrier Proteins; Collectins; Complement C1r; Complement C1s; Complement C3; Evolution, Molecular; Humans; Macromolecular Substances; Mannose-Binding Protein-Associated Serine Proteases; Mice; Phylogeny; Protein Conformation; Sequence Homology, Amino Acid; Serine Endopeptidases; Species Specificity; Urochordata; Vertebrates
PubMed: 9777417
DOI: 10.1016/S0171-2985(98)80038-7 -
Cell Death and Differentiation Mar 2008The HtrA family refers to a group of related oligomeric serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. Mammals... (Review)
Review
The HtrA family refers to a group of related oligomeric serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. Mammals encode four HtrA proteases, named HtrA1-4. The protease activity of the HtrA member HtrA2/Omi is required for mitochondrial homeostasis in mice and humans and inactivating mutations associated with neurodegenerative disorders such as Parkinson's disease. Moreover, HtrA2/Omi is released in the cytosol, where it contributes to apoptosis through both caspase-dependent and -independent pathways. Here, we review the current knowledge of HtrA2/Omi biology and discuss the signaling pathways that underlie its mitochondrial and apoptotic functions from an evolutionary perspective.
Topics: Amino Acid Sequence; Animals; Apoptosis; High-Temperature Requirement A Serine Peptidase 2; Humans; Mice; Mitochondrial Proteins; Molecular Chaperones; Molecular Sequence Data; Neurodegenerative Diseases; Phylogeny; Serine Endopeptidases
PubMed: 18174901
DOI: 10.1038/sj.cdd.4402291 -
Biological & Pharmaceutical Bulletin 2022Vibrio vulnificus is a Gram-negative estuarine bacterium that causes infection in immuno-compromised patients, eels, and shrimp. V. vulnificus NCIMB2137, a...
Vibrio vulnificus is a Gram-negative estuarine bacterium that causes infection in immuno-compromised patients, eels, and shrimp. V. vulnificus NCIMB2137, a metalloprotease-negative strain isolated from a diseased eel, produces a 45-kDa chymotrypsin-like alkaline serine protease known as VvsA. The gene encoding vvsA also includes another gene, vvsB with an unknown function; however, it is assumed to be an essential molecular chaperone for the maturation of VvsA. In the present study, we used an in vitro cell-free translation system to examine the maturation pathway of VvsA. We individually expressed the vvsA and vvsB genes and detected their mRNAs. However, the sample produced from vvsA did not exhibit protease activity. A sodium dodecyl sulfate (SDS) analysis detected the VvsB protein, but not the VvsA protein. A Western blotting analysis using a histidine (His)-tag at the amino terminus of proteins also showed no protein production by vvsA. These results suggested the translation, but not the transcription of vvsA. Factors derived from Escherichia coli were used in the in vitro cell-free translation system employed in the present study. The operon of the serine protease gene containing vvsA and vvsB was expressed in E. coli. Although serine proteases were produced, they were cleaved at different sites and no active mature forms were detected. These results indicate that the operon encoding vvsA and vvsB is a gene constructed to be specifically expressed in V. vulnificus.
Topics: Humans; Vibrio vulnificus; Serine Proteases; Escherichia coli; Serine Endopeptidases
PubMed: 36328494
DOI: 10.1248/bpb.b22-00106 -
Die Pharmazie Dec 2023The global pandemic of COVID-19 disease is caused by the pathogenic factor called SARS-CoV-2. Meanwhile, a series of vaccines and small-molecule drugs, including the... (Review)
Review
The global pandemic of COVID-19 disease is caused by the pathogenic factor called SARS-CoV-2. Meanwhile, a series of vaccines and small-molecule drugs, including the mRNA vaccines and Paxlovid, have been approved, but their efficacy is decreased significantly due to the constant emergence of mutant viral strains. The R&D of host-directed therapeutics has great potential to overcome such limitations and provide new prevention and therapy options for patients with COVID-19 or high-risk group for SARS-CoV-2 infections. Transmembrane serine protease 2 (TMPRSS2) is belonging to a protein family with highly conserved serine protease domain whose crucial role in viral entry is to activate the spike protein of viruses to induce the fusion between host cells and viruses. In this review, we sketch the critical position of TMPRSS2 in the SARS-CoV-2 viral entry and summarize the advanced research and development of TMPRSS2 inhibitors, including repurposed drugs, as a new way to fight COVID-19.
Topics: Humans; COVID-19; Drug Repositioning; Serine Endopeptidases; Serine Proteases; Serine Proteinase Inhibitors
PubMed: 38178286
DOI: 10.1691/ph.2023.3578 -
Microbiology Spectrum Dec 2023Mycoparasites play important roles in the biocontrol of plant fungal diseases, during which they secret multiple hydrolases such as serine proteases to degrade their...
Mycoparasites play important roles in the biocontrol of plant fungal diseases, during which they secret multiple hydrolases such as serine proteases to degrade their fungal hosts. In this study, we demonstrated that the serine protease CrKP43 was involved in development and mycoparasitism with the regulation of Crmapk. To the best of our knowledge, it is the first report on the functions and regulatory mechanisms of serine proteases in . Our findings will provide new insight into the regulatory mechanisms of serine proteases in mycoparasites and contribute to clarifying the mechanisms underlying mycoparasitism of , which will facilitate the development of highly efficient fungal biocontrol agents as well.
Topics: Serine Proteases; Hypocreales; Serine Endopeptidases; Plant Diseases; Fungal Proteins
PubMed: 37831480
DOI: 10.1128/spectrum.02448-23 -
Science Advances Dec 2023Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial...
Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial peptides, respectively, to kill pathogens. These two processes are mediated by phenoloxidase (PO) and SpƤtzle (Spz) through an extracellular network of serine proteases. While some proteases have been identified in in genetic studies, the exact order of proteolytic activation events remains controversial. Here, we reconstituted the serine protease framework in by biochemical methods. This system comprises 10 proteases, i.e., ModSP, cSP48, Grass, Psh, Hayan-PA, Hayan-PB, Sp7, MP1, SPE and Ser7, which form cascade pathways that recognize microbial molecular patterns and virulence factors, and generate PO1, PO2, and Spz from their precursors. Furthermore, the serpin Necrotic negatively regulates the immune response progression by inhibiting ModSP and Grass. The biochemical approach, when combined with genetic analysis, is crucial for addressing problems that long stand in this important research field.
Topics: Animals; Drosophila; Drosophila melanogaster; Drosophila Proteins; Serine Endopeptidases; Serine Proteases
PubMed: 38117884
DOI: 10.1126/sciadv.adk2756