Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis

List, Karin; Haudenschild, Christian C.; Szabo, Roman; Chen, Wanjun; Wahl, Sharon M.; Swaim, William D.; Engelholm, Lars H.; Behrendt, Niels; Bugge, Thomas H.

doi:10.1038/sj.onc.1205502

Cited by 303 publications

(332 citation statements)

References 58 publications

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“…A proteolysis-independent role of HAI-1 in embryonic development has also been proposed (Tanaka et al, 2005), because HAI-1 is an integral transmembrane protein with a cytoplasmic tail domain that is potentially capable of transducing extracellular signals, and because hepatocyte growth factor activator, hepsin, and matriptase are all dispensable for mouse embryonic development (Wu et al, 1998;List et al, 2002;Itoh et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

et al. 2006

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Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with several trypsin-like serine proteases and is required for mouse placental development and embryo survival. Here we show that the essential function of HAI-1 in placentation and all other embryonic processes is to restrict the activity of the type II transmembrane serine protease, matriptase. Enzymatic gene trapping of matriptase combined with HAI-1 immunohistochemistry revealed that matriptase is coexpressed with HAI-1 in both extraembryonic and embryonic tissues. As early as embryonic day 8.5, matriptase and HAI-1 were expressed in a population of chorionic trophoblasts. Ablation of HAI-1 disrupted the epithelial integrity of this cell population, causing disorganized laminin deposition and altered expression of E-cadherin and b-catenin. This led to a complete loss of undifferentiated chorionic trophoblasts after embryonic day 9.5 and prevented the formation of the placental labyrinth. Genetic ablation of matriptase activity in HAI-1-deficient embryos, however, restored the integrity of chorionic trophoblasts and enabled placental labyrinth formation and development to term. Furthermore, matriptase/HAI-1 double-deficient mice were phenotypically indistinguishable from matriptase single-deficient littermates.

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Section: Introductionmentioning

confidence: 99%

“…Gene targeting studies in mice have revealed an essential role of the protease in postnatal oral and epidermal barrier formation and hair follicle growth (List et al, 2002(List et al, , 2006. However, matriptasedeficient mice develop to term, and they display no obvious developmental abnormalities besides the skin and oral cavity.…”

Section: Introductionmentioning

confidence: 99%

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

et al. 2006

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“…6−8 Matriptase or MT-SP1 is a type II transmembrane serine protease (TTSP) that is mainly expressed in the epidermis, thymic stroma, and other epithelia. 9,10 The proteolytic activity of matriptase is controlled by hepatocyte growth factor activator inhibitor-1 (HAI-1). 9,10 Knockout mouse studies have revealed that matriptase plays a role in terminal differentiation of epidermis, hair follicle development, and thymic homeostasis.…”

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confidence: 99%

“…9,10 The proteolytic activity of matriptase is controlled by hepatocyte growth factor activator inhibitor-1 (HAI-1). 9,10 Knockout mouse studies have revealed that matriptase plays a role in terminal differentiation of epidermis, hair follicle development, and thymic homeostasis. 9 Relative ratio of matriptase to HAI-1 is reported to be higher in a range of epithelial tumors, in which active matriptase plays an important role in cellular invasion and metastasis.…”

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confidence: 99%

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors

Goswami

Mukherjee

Wohlfahrt

et al. 2013

ACS Med. Chem. Lett.

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Matriptase belongs to trypsin-like serine proteases involved in matrix remodeling/degradation, growth regulation, survival, motility, and cell morphogenesis. Herein, we report a structure-based approach, which led to the discovery of sulfonamide and amide derivatives of pyridyl bis(oxy)-benzamidine as potent and selective matriptase inhibitors. Co-crystal structures of selected compounds in complex with matriptase supported compound designing. Additionally, WaterMap analyses indicated the possibility of occupying a distinct pocket within the catalytic domain, exploration of which resulted in >100-fold improvement in potency. Co-crystal structure of 10 with matriptase revealed critical interactions leading to potent target inhibition and selectivity against other serine proteases.

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“…Indeed, mice lacking St14 (matriptase) or Prss8 (prostasin) genes showed a severe defect in epidermal barrier function and died from dehydration early in neonatal development. 36,37 In humans, amino acid substitutions in the highly conserved protease domain of matriptase result in reduction or loss of matriptase activity and cause autosomal recessive ichthyosis with hypotrichosis. 38 On the other hand, excess expression or activity of serine protease is associated with skin disorders.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Kawaguchi

Kanemaru

Sawaguchi

et al. 2015

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membraneassociated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI-1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1edeficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2edependent p38 mitogen-activated protein kinase signaling. Human skin protects the body from both water loss and mechanical damage. This barrier function is primarily accomplished by the epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes. 1 To achieve the barrier functions, keratinocytes form dynamic and strong cell-cell junctions in which desmosomes and the network of keratin intermediate filaments (KIFs) are essential to maintain junctional integrity. 2 KIFs are anchored to the cytoplasm and interact with desmosomal cell-cell contacts at the plasma membrane. These are important for mechanical stability of cell-cell contacts between keratinocytes. 3 Disturbance of the integrity of the KIF network leads to skin-blistering diseases, such as epidermolysis bullosa simplex. 4 Although it is not known how KIF disassembly is regulated, recent studies suggested that p38 mitogen-activated protein kinase (MAPK) signaling is involved in these processes. 4e6 The p38 is a member of the MAPK family. It is present in epithelial cells, responds rapidly to various types of stresses,

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Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis

Cited by 303 publications

References 58 publications

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Discovery of Pyridyl Bis(oxy)dibenzimidamide Derivatives as Selective Matriptase Inhibitors

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

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