Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

Hobson, John P.; Netzel‐Arnett, Sarah; Szabo, Roman; Réhault, Sophie; Church, Frank C.; Strickland, Dudley K.; Lawrence, Daniel A.; Antalis, Toni M.; Bugge, Thomas H.

doi:10.1074/jbc.m403299200

Cited by 48 publications

(61 citation statements)

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“…At present, a number of serine proteases have been identified on sperm acrosome, and some of them are embedded in the plasma membrane or the outer acrosomal membrane, composing a lytic consortium on the apical surface of the sperm (63)(64)(65)(66). Protease activation and inhibition must be precise in time and place.…”

Section: Discussionmentioning

confidence: 99%

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

et al. 2013

Journal of Biological Chemistry

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Background:The molecular mechanism involved in sperm maturation is still not completely elucidated. Results:We identified an epididymis-specific gene, Spink13, that is essential for the acrosomal integrity and sperm maturation. Conclusion: Our findings provided direct evidence of a modulatory effect of SPINK13 on fertilization. Significance: We expect further study of SPINK13 will provide a new putative target for post-testicular male contraceptives.

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Section: Discussionmentioning

confidence: 99%

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

et al. 2013

Journal of Biological Chemistry

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“…11,12 Other members of this protease family whose physiologic and pathologic roles still remain unclear are spinesin/TMPRSS5, 13 MSPL (mosaic serine protease large form), 14 matriptase-3, 15 polyserase-1, 16 as well as the different components of the HAT (human airway trypsin-like protease)/DESC (differentially expressed in squamous cell carcinoma) subfamily. 17,18 Matriptase-2 (TMPRSS6) is another TTSP family member of unknown function, but whose study has achieved particular interest because of its structural and enzymatic similarities with matriptase and to its putative role as a tumor suppressor enzyme in human breast cancer. [19][20][21] This enzyme was first identified and cloned in our laboratory 19 as part of our ongoing studies aimed at characterizing the human degradome, which is defined as the complete set of proteases produced by human cells.…”

Section: Introductionmentioning

confidence: 99%

Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis

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et al. 2008

Blood

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Proteolytic events at the cell surface are essential in the regulation of signal transduction pathways. During the past years, the family of type II transmembrane serine proteases (TTSPs) has acquired an increasing relevance because of their privileged localization at the cell surface, although our current understanding of the biologic function of most TTSPs is limited. Here we show that matriptase-2 (Tmprss6), a recently described member of the TTSP family, is an essential regulator of iron homeostasis. Thus, Tmprss6 Ϫ/Ϫ mice display an overt phenotype of alopecia and a severe iron deficiency anemia. These hematologic alterations found in Tmprss6 Ϫ/Ϫ mice are accompanied by a marked up-regulation of hepcidin, a negative regulator of iron export into plasma. Likewise, Tmprss6 Ϫ/Ϫ mice have reduced ferroportin expression in the basolateral membrane of enterocytes and accumulate iron in these cells. Iron-dextran therapy rescues both alopecia and hematologic alterations of Tmprss6 Ϫ/Ϫ mice, providing causal evidence that the anemic phenotype of these mutant mice results from the blockade of intestinal iron export into plasma after dietary absorption. On the basis of these findings, we conclude that matriptase-2 activity represents a novel and relevant step in hepcidin regulation and iron homeostasis. IntroductionPericellular proteolysis is an essential event that determines the relations between the cell and its microenvironment. This crucial process in the development and maintenance of multicellular organisms requires the remodeling of extracellular matrix components as well as the posttranslational regulation of a wide range of cell-surface receptors, regulatory proteins, and adhesion molecules. 1 The increasing relevance of proteolytic processes localized at the cell surface has attracted notable attention on membraneassociated proteolytic systems, including the family of type II transmembrane serine proteases (TTSPs). 2,3 The TTSP family is composed of more than 20 different members that share a number of structural features: a single-pass transmembrane domain located near the short cytoplasmic amino-terminal tail, a central region containing different protein-interacting domains, and a carboxyterminal catalytic region with the structural characteristics of serine proteases. The large variability of the central modular region together with the diverse expression patterns of TTSP family members suggest that these enzymes may play different physiologic and pathologic roles, although only a few of these functions have been identified so far. Thus, enteropeptidase is mainly expressed in the duodenum and plays an essential role in food digestion as activator of pancreatic trypsinogen to trypsin. 4 Hepsin, is mainly expressed in liver, but it is highly up-regulated in prostate cancer. 5,6 Matriptase/MT-SP1 is a widely studied member of the TTSP family because of its relevance in diverse processes, including cancer progression. 7,8 Mutant mice deficient in matriptase die shortly after birth because of aberrant skin ...

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“…Moreover, we can not rule out that DESC1 could likewise be involved in proteolytic cascades that would include protease inhibitor as happens with matriptase (Netzel-Arnett et al, 2006). In this regard, the mouse counterpart of this protease, mDESC1, forms stable inhibitory complexes with both plasminogen activator inhibitor-1 and protein C inhibitor (Hobson et al, 2004). These observations raise new intriguing questions about the role of DESC1 in normal and pathological processes.…”

Section: Discussionmentioning

confidence: 98%

“…Thus, matriptase is an essential enzyme for postnatal survival, epidermal barrier function, hair follicle development and thymic homeostasis in mice (List et al, 2002; HAT (human airway trypsin-like protease) has been proposed to play a role in host immune defence (Yamaoka et al, 1998); corin regulates blood pressure by activating the cardiac hormone pro-ANP (Yan et al, 2000); and TMPRSS3 has been suggested to be involved in inner ear development (Guipponi et al, 2002). Likewise, the role of the TTSP in tumour growth, cancer invasion and metastasis processes are being increasingly documented for proteases such as matriptase (List et al, 2005), matriptase-2 (Velasco et al, 2002) and hepsin (Hobson et al, 2004;Klezovitch et al, 2004).…”

mentioning

confidence: 99%

“…The HAT/DESC constitutes a phylogenetically related subfamily of TTSP with five DESC1 (differentially expressed in squamous cell carcinoma gene 1)-like genes clustered within a region in the chromosome 4q (Behrens et al, 2004;Hobson et al, 2004). DESC1 was identified through the reduced levels of associated mRNA present in tumours from diverse sites in the head and neck region when compared with corresponding normal tissue (Lang and Schuller, 2001).…”

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Human DESC1 serine protease confers tumorigenic properties to MDCK cells and it is upregulated in tumours of different origin

et al. 2007

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Proteolysis of the extracellular matrix components plays a crucial role in the regulation of the cellular and physiological processes, and different pathologies have been associated with the loss or gain of function of proteolytic enzymes. DESC1 (differentially expressed in squamous cell carcinoma gene 1), a member of the TTSP (type II transmembrane serine protease) family of serine proteases, is an epithelial-specific enzyme that has been found downregulated in squamous cell carcinoma of the head and neck region. We describe new properties of DESC1 suggesting that this protease may be involved in the progression of some type of tumours. Thus, this enzyme hydrolyses some extracellular matrix components, such as fibronectin, gelatin or fibrinogen. Moreover, Madin -Darby canine kidney (MDCK) cells expressing exogenous human DESC1 acquire properties associated with tumour growth such as enhanced motility and an increase of tubular forms in a 3D collagen lattice following HGF treatment. Finally, we generated polyclonal anti-DESC1 antibodies and immunohistochemical analysis in tissues different from head and neck region indicated that this protease was overexpressed in tumours of diverse origins. Taken together, our results suggest that DESC1 could be considered as a potential therapeutic target in some type of tumours.

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Mouse DESC1 Is Located within a Cluster of Seven DESC1-like Genes and Encodes a Type II Transmembrane Serine Protease That Forms Serpin Inhibitory Complexes

Cited by 48 publications

References 54 publications

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

Spink13, an Epididymis-specific Gene of the Kazal-type Serine Protease Inhibitor (SPINK) Family, Is Essential for the Acrosomal Integrity and Male Fertility

Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis

Human DESC1 serine protease confers tumorigenic properties to MDCK cells and it is upregulated in tumours of different origin

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