Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

Kawaguchi, Makiko; Takeda, Nobuo; Hoshiko, Shinri; Yorita, Kenji; Baba, Takashi; Sawaguchi, Akira; Nezu, Yuriko; Yoshikawa, Tsutomu; Fukushima, Tsuyoshi; Kataoka, Hiroaki

doi:10.1016/j.ajpath.2011.06.038

Cited by 44 publications

(48 citation statements)

References 41 publications

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“…−/− placentas display phenotypic hallmarks of Spint1 deficiency Spint1 encodes a cell membrane-associated Kunitz type 1 serine protease inhibitor (Shimomura et al, 1997) that is expressed in several epithelial cells and tissues, including the placenta, kidney and intestine (Kataoka et al, 2000;Yamauchi et al, 2004;Oberst et al, 2005;Szabo et al, 2007;Kawaguchi et al, 2011). Similar to Grhl2 −/− placentas, chorionic trophoblasts of Spint1 −/− placentas fail to establish a labyrinth, fetal vascularization is absent, and the trophoblast layer appears to be compact (Tanaka et al, 2005;Fan et al, 2007;Szabo et al, 2007).…”

Section: Grhl2mentioning

confidence: 99%

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

et al. 2015

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Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction

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Section: Grhl2mentioning

confidence: 99%

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

et al. 2015

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“…Matriptase, encoded by the ST14 gene, belongs to the type II transmembrane serine protease superfamily and is expressed on the epithelial cell surface of most epithelial tissues (6). Moreover, recent studies indicate that its cognate cell surface inhibitor, hepatocyte growth factor activator inhibitor (HAI), also has crucial roles in epithelial functions (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…Unlike HAI-2/ SPINT2, HAI-1/SPINT1 also has an N-terminal cysteine-rich domain and a low-density lipoprotein receptor type A-like domain (11). HAI-1/SPINT1 is expressed in most epithelial cells, with significant expression in enterocytes (8,12). HAI-1/ SPINT1 was initially discovered as an endogenous inhibitor of HGF activator, a serum-derived serine protease (13), but its membrane association may also allow it to regulate cell surface serine proteases.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, HAI-1/SPINT1 has essential functions in placental trophoblasts, epidermal keratinocytes, and hair follicle epithelium (7,21). Recently, we reported that conditional deletion of the Spint1 gene in intestinal epithelial cells results in enhanced intestinal permeability and susceptibility to dextran sulfate sodium (DSS)-induced colitis (8). As intestinal epithelial integrity has an important protective role against mucosal inflammation and neoplastic progression (1,2,22), HAI-1/SPINT1 may have a significant role in intestinal tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis

et al. 2013

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane-bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine ApcMin/þ tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non-neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on Apc Min/þ mice. The loss ofHai-1/Spint1 significantly accelerated tumor formation in Apc Min/þ mice and shortened their survival periods.Activation of HGF was enhanced in Hai-1/Spint1-deficient Apc Min/þ intestine. Gene expression profiling revealed upregulation of the Wnt/b-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1-deficient Apcintestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli. Cancer Res; 73(8); 2659-70. Ó2013 AACR.

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“…14e20 By using Spint1 mutant mouse models, we previously reported that HAI-1 is critically required in the development of the placental labyrinth 21 and normal keratinization of the skin, 22 and it may also contribute to intestinal epithelial barrier function. 23 In the absence of HAI-1, epidermis showed hyperkeratosis and decreased barrier function in mice. 22 Moreover, hair cuticle formation was severely impaired.…”

mentioning

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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Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

Cited by 44 publications

References 41 publications

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

A Grhl2-dependent gene network controls trophoblast branching morphogenesis

Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis

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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