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  1. Article ; Online: The spatiotemporal control of human matriptase action on its physiological substrates: a case against a direct role for matriptase proteolytic activity in profilaggrin processing and desquamation.

    Lin, Chen-Yong / Wang, Jehng-Kang / Johnson, Michael D

    Human cell

    2020  Volume 33, Issue 3, Page(s) 459–469

    Abstract: Studies of human genetic disorders and animal models indicate that matriptase plays essential roles in proteolytic processes associated with profilaggrin processing and desquamation at late stages of epidermal differentiation. The tissue distribution ... ...

    Abstract Studies of human genetic disorders and animal models indicate that matriptase plays essential roles in proteolytic processes associated with profilaggrin processing and desquamation at late stages of epidermal differentiation. The tissue distribution profile and zymogen activation status in human skin, however, suggests that matriptase physiological function in the skin more likely lies in the proliferating and differentiating keratinocytes in the basal and spinous layers. Marked acanthosis with expanded spinous layer and lack of significant changes in intensity and expression pattern for several terminal differentiation markers in the skin of ARIH patients support matriptase's role in earlier rather than the later stages of differentiation. In addition to the tissue distribution, differential subcellular localization further limits the ability of extracellular matriptase proteolytic activity to access the cytosolic non-membrane-bound keratohyalin granules, in which profilaggrin processing occurs. The short lifespan of active matriptase, which results from tightly controlled zymogen activation, rapid inhibition by HAI-1, and shedding from cell surface, indicates that active matriptase likely performs physiological functions via limited proteolysis on its substrates, as needed, rather than via a continuous bulk process. We, here, review these spatiotemporal controls of matriptase proteolytic activity at the biochemical, cellular, and tissue level. Based on this in-depth understanding of how matriptase activity is regulated, we argue that there is no direct involvement of matriptase proteolytic activity in profilaggrin processing and desquamation. The defects in epidermal terminal differentiation associated with matriptase deficiency are likely secondary and are due to putative disruption at earlier stages of differentiation.
    MeSH term(s) Animals ; Cell Differentiation ; Cell Proliferation ; Enzyme Precursors/metabolism ; Epidermal Cells/physiology ; Humans ; Intermediate Filament Proteins/metabolism ; Keratinocytes/physiology ; Mice ; Mutation ; Proteolysis ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Serine Endopeptidases/physiology
    Chemical Substances Enzyme Precursors ; Intermediate Filament Proteins ; filaggrin ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-)
    Language English
    Publishing date 2020-04-18
    Publishing country Japan
    Document type Journal Article ; Review
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-020-00361-7
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3676: Show issues Location:
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  2. Article ; Online: N-glycosylation on Asn-57 is required for the correct HAI-2 protein folding and protease inhibitory activity.

    Huang, Nanxi / Wang, Qiaochu / Chen, Chao-Yang / Hu, Je-Ming / Wang, Jehng-Kang / Chang, Ping-Ying / Johnson, Michael D / Lin, Chen-Yong

    Glycobiology

    2023  Volume 33, Issue 3, Page(s) 203–214

    Abstract: Hepatocyte growth factor activator inhibitor (HAI)-2 is an integral membrane Kunitz-type serine protease inhibitor that regulates the proteolysis of matriptase and prostasin in a cell-type selective manner. The cell-type selective nature of HAI-2 ... ...

    Abstract Hepatocyte growth factor activator inhibitor (HAI)-2 is an integral membrane Kunitz-type serine protease inhibitor that regulates the proteolysis of matriptase and prostasin in a cell-type selective manner. The cell-type selective nature of HAI-2 function depends largely on whether the inhibitor and potential target enzymes are targeted to locations in close proximity. The N-glycan moiety of HAI-2 can function as a subcellular targeting signal. HAI-2 is synthesized with 1 of 2 different N-glycan modifications: one of oligomannose-type, which largely remains in the endoplasmic reticulum/GA, and another of complex-type, which is targeted toward the apical surface in vesicle-like structures, and could function as an inhibitor of matriptase and prostasin. HAI-2 contains 2 putative N-glycosylation sites, Asn-57 and Asn-94, point mutations of which were generated and characterized in this study. The protein expression profile of the HAI-2 mutants indicates that Asn-57, and not Asn-94, is responsible for the N-glycosylation of both HAI-2 species, suggesting that the form with oligomannose-type N-glycan is the precursor of the form with complex-type N-glycan. Unexpectedly, the vast majority of non-glycosylated HAI-2 is synthesized into multiple disulfide-linked oligomers, which lack protease inhibitory function, likely due to distorted conformations caused by the disarrayed disulfide linkages. Although forced expression of HAI-2 in HAI-2 knockout cells artificially enhances HAI-2 oligomerization, disulfide-linked HAI-2 oligomers can also be observed in unmodified cells. These results suggest that N-glycosylation on Asn-57 is required for folding into a functional HAI-2 with full protease suppressive activity and correct subcellular targeting signal.
    MeSH term(s) Membrane Glycoproteins/chemistry ; Proteolysis ; Glycosylation ; Endoplasmic Reticulum/metabolism ; Polysaccharides/metabolism
    Chemical Substances Membrane Glycoproteins ; Polysaccharides
    Language English
    Publishing date 2023-01-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1067689-2
    ISSN 1460-2423 ; 0959-6658
    ISSN (online) 1460-2423
    ISSN 0959-6658
    DOI 10.1093/glycob/cwad002
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    Zs.A 3150: Show issues Location:
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  3. Article ; Online: SPINT2 mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation.

    Huang, Nanxi / Wang, Qiaochu / Bernard, Robert B / Chen, Chao-Yang / Hu, Je-Ming / Wang, Jehng-Kang / Chan, Khee-Siang / Johnson, Michael D / Lin, Chen-Yong

    Human molecular genetics

    2024  Volume 33, Issue 9, Page(s) 752–767

    Abstract: Mutations in the Kunitz-type serine protease inhibitor HAI-2, encoded by SPINT2, are responsible for the pathogenesis of syndromic congenital sodium diarrhea (SCSD), an intractable secretory diarrhea of infancy. Some of the mutations cause defects in the ...

    Abstract Mutations in the Kunitz-type serine protease inhibitor HAI-2, encoded by SPINT2, are responsible for the pathogenesis of syndromic congenital sodium diarrhea (SCSD), an intractable secretory diarrhea of infancy. Some of the mutations cause defects in the functionally required Kunitz domain 1 and/or subcellular targeting signals. Almost all SCSD patients, however, harbor SPINT2 missense mutations that affect the functionally less important Kunitz domain 2. How theses single amino acid substitutions inactivate HAI-2 was, here, investigated by the doxycycline-inducible expression of three of these mutants in HAI-2-knockout Caco-2 human colorectal adenocarcinoma cells. Examining protein expressed from these HAI-2 mutants reveals that roughly 50% of the protein is synthesized as disulfide-linked oligomers that lose protease inhibitory activity due to the distortion of the Kunitz domains by disarrayed disulfide bonding. Although the remaining protein is synthesized as monomers, its glycosylation status suggests that the HAI-2 monomer remains in the immature, lightly glycosylated form, and is not converted to the heavily glycosylated mature form. Heavily glycosylated HAI-2 possesses full anti-protease activity and appropriate subcellular targeting signals, including the one embedded in the complex-type N-glycan. As predicted, these HAI-2 mutants cannot suppress the excessive prostasin proteolysis caused by HAI-2 deletion. The oligomerization and glycosylation defects have also been observed in a colorectal adenocarcinoma line that harbors one of these SPINT2 missense mutations. Our study reveals that the abnormal protein folding and N-glycosylation can cause widespread HAI-2 inactivation in SCSD patents.
    MeSH term(s) Humans ; Membrane Glycoproteins/metabolism ; Caco-2 Cells ; Glycosylation ; Mutation ; Diarrhea/congenital ; Protein Folding ; Adenocarcinoma ; Colorectal Neoplasms/genetics ; Disulfides ; Proteinase Inhibitory Proteins, Secretory/genetics ; Serine Endopeptidases
    Chemical Substances prostasin (EC 3.4.21.-) ; Membrane Glycoproteins ; Disulfides ; Proteinase Inhibitory Proteins, Secretory ; SPINT2 protein, human ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2024-01-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddae005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3469: Show issues Location:
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  4. Article ; Online: Role of the polycystic kidney disease domain in matriptase chaperone activity and localization of hepatocyte growth factor activator inhibitor‐1

    Yamashita, Fumiki / Kaieda, Takashi / Shimomura, Takeshi / Kawaguchi, Makiko / Lin, Chen‐Yong / Johnson, Michael D. / Tanaka, Hiroyuki / Kiwaki, Takumi / Fukushima, Tsuyoshi / Kataoka, Hiroaki

    FEBS journal. 2022 June, v. 289, no. 12 p.3422-3439

    2022  

    Abstract: Hepatocyte growth factor activator inhibitor‐1 (HAI‐1, also known as SPINT1) is an inhibitor of matriptase, a type‐2 transmembrane protease widely expressed in epithelial cells. HAI‐1 also functions as a chaperone to maintain the processing and ... ...

    Abstract Hepatocyte growth factor activator inhibitor‐1 (HAI‐1, also known as SPINT1) is an inhibitor of matriptase, a type‐2 transmembrane protease widely expressed in epithelial cells. HAI‐1 also functions as a chaperone to maintain the processing and localization of matriptase required for epithelial integrity. However, mechanisms underpinning the chaperone function remain to be elucidated. Here, we show that the first Kunitz domain (KD1) and the adjacent polycystic kidney disease (PKD) domain‐like internal domain of HAI‐1 are essential for the chaperone function. In HEK293T cells, which do not express endogenous HAI‐1 or matriptase, forced matriptase overexpression was unsuccessful unless sufficient HAI‐1 was co‐expressed. Among mutant HAI‐1 constructs, HAI‐1 with inactivation mutation in KD1 (HAI‐1mKD1) or HAI‐1 lacking the PKD domain (HAI‐1dPKD) was unable to support matriptase expression, and neither mutant formed a complex with activated matriptase. Matriptase did not localize to the cell surface when co‐expressed with HAI‐1dPKD. Moreover, HAI‐1dPKD accumulated in the cytoplasm of HEK293T and HaCaT cells rather than localizing to the cell surface, presumably due to misfolding as judged by altered antibody recognition. On the other hand, activationlocked and activity‐incompetent matriptase were stable and readily overexpressed and localized to the cell surface without HAI‐1. Therefore, the observed matriptase instability was caused by its own catalytic activity in the absence of inhibitory HAI‐1. The matriptase chaperone function of HAI‐1 is thus mediated primarily by the inhibition of undesired intracellular matriptase activity, and the PKD domain is essential for the proper folding and trafficking of inhibitory HAI‐1 and its chaperone function.
    Keywords antibodies ; catalytic activity ; cytoplasm ; epithelium ; hepatocyte growth factor ; mutants ; mutation ; polycystic kidney diseases ; proteinases
    Language English
    Dates of publication 2022-06
    Size p. 3422-3439.
    Publishing place John Wiley & Sons, Ltd
    Document type Article ; Online
    Note REVIEW
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16348
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  5. Article ; Online: HAI-1 is required for the novel role of FGFBP1 in maintenance of cell morphology and F-actin rearrangement in human keratinocytes.

    Lu, Dajun D / Huang, Nanxi / Li, Sheng-Wen A / Fang, Jessica R / Lai, Chih-Hsin / Wang, Jehng-Kang / Chan, Khee-Siang / Johnson, Michael D / Lin, Chen-Yong

    Human cell

    2023  Volume 36, Issue 4, Page(s) 1403–1415

    Abstract: Formation and maintenance of skin barrier function require tightly controlled membrane-associated proteolysis, in which the integral membrane Kunitz-type serine protease inhibitor, HAI-1, functions as the primary inhibitor of the membrane-associated ... ...

    Abstract Formation and maintenance of skin barrier function require tightly controlled membrane-associated proteolysis, in which the integral membrane Kunitz-type serine protease inhibitor, HAI-1, functions as the primary inhibitor of the membrane-associated serine proteases, matriptase and prostasin. Previously, HAI-1 loss in HaCaT human keratinocytes resulted in an expected increase in prostasin proteolysis but a paradoxical decrease in matriptase proteolysis. The paradoxical decrease in shed active matriptase is further investigated in this study with an unexpected discovery of novel functions of fibroblast growth factor-binding protein 1 (FGFBP1), which acts as an extracellular ligand that can rapidly elicit F-actin rearrangement and subsequently affect the morphology of human keratinocytes. This novel growth factor-like function is in stark contrast to the canonical activity of this protein through interactions with FGFs for its pathophysiological functions. This discovery began with the observation that HAI-1 KO HaCaT cells lose the characteristic cobblestone morphology of the parental cells and exhibit aberrant F-actin formation along with altered subcellular targeting of matriptase and HAI-2. The alterations in cell morphology and F-actin status caused by targeted HAI-1 deletion can be restored by treatment with conditioned medium from parental HaCaT cells, in which FGFBP1 was identified by tandem mass spectrometry. Recombinant FGFBP1 down to 1 ng/ml was able to revert the changes caused by HAI-1 loss. Our study reveals a novel function of FGFBP1 in the maintenance of keratinocyte morphology, which depends on HAI-1.
    MeSH term(s) Humans ; Actins/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Keratinocytes/metabolism ; Proteolysis ; Proteinase Inhibitory Proteins, Secretory/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism
    Chemical Substances Actins ; Membrane Glycoproteins ; Proteinase Inhibitory Proteins, Secretory ; FGFBP1 protein, human (139946-12-6) ; Intercellular Signaling Peptides and Proteins
    Language English
    Publishing date 2023-04-19
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-023-00906-6
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    Zs.A 3676: Show issues Location:
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  6. Article ; Online: Role of the polycystic kidney disease domain in matriptase chaperone activity and localization of hepatocyte growth factor activator inhibitor-1.

    Yamashita, Fumiki / Kaieda, Takashi / Shimomura, Takeshi / Kawaguchi, Makiko / Lin, Chen-Yong / Johnson, Michael D / Tanaka, Hiroyuki / Kiwaki, Takumi / Fukushima, Tsuyoshi / Kataoka, Hiroaki

    The FEBS journal

    2022  Volume 289, Issue 12, Page(s) 3422–3439

    Abstract: Hepatocyte growth factor activator inhibitor-1 (HAI-1, also known as SPINT1) is an inhibitor of matriptase, a type-2 transmembrane protease widely expressed in epithelial cells. HAI-1 also functions as a chaperone to maintain the processing and ... ...

    Abstract Hepatocyte growth factor activator inhibitor-1 (HAI-1, also known as SPINT1) is an inhibitor of matriptase, a type-2 transmembrane protease widely expressed in epithelial cells. HAI-1 also functions as a chaperone to maintain the processing and localization of matriptase required for epithelial integrity. However, mechanisms underpinning the chaperone function remain to be elucidated. Here, we show that the first Kunitz domain (KD1) and the adjacent polycystic kidney disease (PKD) domain-like internal domain of HAI-1 are essential for the chaperone function. In HEK293T cells, which do not express endogenous HAI-1 or matriptase, forced matriptase overexpression was unsuccessful unless sufficient HAI-1 was co-expressed. Among mutant HAI-1 constructs, HAI-1 with inactivation mutation in KD1 (HAI-1mKD1) or HAI-1 lacking the PKD domain (HAI-1dPKD) was unable to support matriptase expression, and neither mutant formed a complex with activated matriptase. Matriptase did not localize to the cell surface when co-expressed with HAI-1dPKD. Moreover, HAI-1dPKD accumulated in the cytoplasm of HEK293T and HaCaT cells rather than localizing to the cell surface, presumably due to misfolding as judged by altered antibody recognition. On the other hand, activationlocked and activity-incompetent matriptase were stable and readily overexpressed and localized to the cell surface without HAI-1. Therefore, the observed matriptase instability was caused by its own catalytic activity in the absence of inhibitory HAI-1. The matriptase chaperone function of HAI-1 is thus mediated primarily by the inhibition of undesired intracellular matriptase activity, and the PKD domain is essential for the proper folding and trafficking of inhibitory HAI-1 and its chaperone function.
    MeSH term(s) HEK293 Cells ; Humans ; Polycystic Kidney Diseases/metabolism ; Proteinase Inhibitory Proteins, Secretory/metabolism ; Serine Endopeptidases/metabolism
    Chemical Substances Proteinase Inhibitory Proteins, Secretory ; SPINT1 protein, human ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-)
    Language English
    Publishing date 2022-01-23
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.16348
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 260: Show issues Location:
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  7. Article ; Online: Rapid Assessment of Surface Markers on Cancer Cells Using Immuno-Magnetic Separation and Multi-frequency Impedance Cytometry for Targeted Therapy.

    Lin, Zhongtian / Lin, Siang-Yo / Xie, Pengfei / Lin, Chen-Yong / Rather, Gulam M / Bertino, Joseph R / Javanmard, Mehdi

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 3015

    Abstract: The rapid qualitative assessment of surface markers on cancer cells can allow for point-of-care prediction of patient response to various cancer drugs. Preclinical studies targeting cells with an antibody to "activated" matriptase conjugated to a potent ... ...

    Abstract The rapid qualitative assessment of surface markers on cancer cells can allow for point-of-care prediction of patient response to various cancer drugs. Preclinical studies targeting cells with an antibody to "activated" matriptase conjugated to a potent toxin show promise as a selective treatment for a variety of solid tumors. In this paper, we implemented a novel technique for electrical detection of proteins on surfaces of cancer cells using multi-frequency microfluidic impedance cytometry. The biosensor, consists of two gold microelectrodes on a glass substrate embedded in a PDMS microfluidic channel, is used in conjugation with immuno-magnetic separation of cancer cells, and is capable of differentiating between bare magnetic beads, cancer cells and bead-cell aggregates based on their various impedance and frequency responses. We demonstrated proof-of-concept based on detection of "activated" matriptase proteins on the surface of cultured Mantle cells.
    MeSH term(s) Biomarkers/metabolism ; Cell Line, Tumor ; Electric Impedance ; Electrodes ; Flow Cytometry ; Humans ; Immunomagnetic Separation ; Microtechnology ; Models, Theoretical ; Molecular Targeted Therapy ; Serine Endopeptidases/metabolism ; Signal-To-Noise Ratio
    Chemical Substances Biomarkers ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-)
    Language English
    Publishing date 2020-02-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-57540-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The difference in the intracellular Arg/Lys-rich and EHLVY motifs contributes to distinct subcellular distribution of HAI-1 versus HAI-2.

    Huang, Nanxi / Barndt, Robert B / Lu, Dajun D / Wang, Qiaochu / Huang, Shih-Ming / Wang, Jehng-Kang / Chang, Ping-Ying / Chen, Chao-Yang / Hu, Je-Ming / Su, Hui-Chen / Johnson, Michael D / Lin, Chen-Yong

    Human cell

    2021  Volume 35, Issue 1, Page(s) 163–178

    Abstract: The integral membrane, Kunitz-type, serine protease inhibitors, HAI-1 and HAI-2, closely resemble one another structurally and with regard to their specificity and potency against proteases. Structural complementarity between the Kunitz domains and ... ...

    Abstract The integral membrane, Kunitz-type, serine protease inhibitors, HAI-1 and HAI-2, closely resemble one another structurally and with regard to their specificity and potency against proteases. Structural complementarity between the Kunitz domains and serine protease domains renders the membrane-associated serine proteases, matriptase and prostasin, the primary target proteases of the HAIs. The shared biochemical enzyme-inhibitor relationships are, however, at odds with their behavior at the cellular level, where HAI-1 appears to be the default inhibitor of these proteases and HAI-2 a cell-type-selective inhibitor, even though they are widely co-expressed. The limited motility of these proteins caused by their membrane anchorages may require their co-localization within a certain distance to allow the establishment of a cellular level functional relationship between the proteases and the inhibitors. The differences in their subcellular localization with HAI-1 both inside the cell and on the cell surface, compared to HAI-2 predominately in intracellular granules has, therefore, been implicated in the differential manner of their control of matriptase and prostasin proteolysis. The targeting signals present in the intracellular domains of the HAIs are systematically investigated herein. Studies involving domain swap and point mutation, in combination with immunocytochemistry and cell surface biotinylation/avidin depletion, reveal that the different subcellular localization between the HAIs can largely be attributed to differences in the intracellular Arg/Lys-rich and EHLVY motifs. These intrinsic differences in the targeting signal render the HAIs as two independent rather than redundant proteolysis regulators.
    MeSH term(s) Amino Acid Motifs ; Arginine/metabolism ; Avidin/metabolism ; Biotinylation ; Cell Membrane/metabolism ; Cells, Cultured ; Cytoplasmic Granules/metabolism ; Humans ; Intracellular Space/metabolism ; Lysine/metabolism ; Membrane Glycoproteins/metabolism ; Protein Domains ; Proteinase Inhibitory Proteins, Secretory/metabolism ; Proteolysis ; Serine Endopeptidases/metabolism
    Chemical Substances Membrane Glycoproteins ; Proteinase Inhibitory Proteins, Secretory ; SPINT1 protein, human ; SPINT2 protein, human ; Avidin (1405-69-2) ; Arginine (94ZLA3W45F) ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-) ; prostasin (EC 3.4.21.-) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2021-10-13
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-021-00632-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3676: Show issues Location:
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  9. Article ; Online: Targeted deletion of HAI-1 increases prostasin proteolysis but decreases matriptase proteolysis in human keratinocytes.

    Lu, Dajun D / Gu, Yayun / Li, Sheng-Wen A / Barndt, Robert J / Huang, Shih-Ming / Wang, Jehng-Kang / Su, Hui Chen / Johnson, Michael D / Lin, Chen-Yong

    Human cell

    2021  Volume 34, Issue 3, Page(s) 771–784

    Abstract: Epidermal differentiation and barrier function require well-controlled matriptase and prostasin proteolysis, in which the Kunitz-type serine protease inhibitor HAI-1 represents the primary enzymatic inhibitor for both proteases. HAI-1, however, also ... ...

    Abstract Epidermal differentiation and barrier function require well-controlled matriptase and prostasin proteolysis, in which the Kunitz-type serine protease inhibitor HAI-1 represents the primary enzymatic inhibitor for both proteases. HAI-1, however, also functions as a chaperone-like protein necessary for normal matriptase synthesis and intracellular trafficking. Furthermore, other protease inhibitors, such as antithrombin and HAI-2, can also inhibit matriptase and prostasin in solution or in keratinocytes. It remains unclear, therefore, whether aberrant increases in matriptase and prostasin enzymatic activity would be the consequence of targeted deletion of HAI-1 and so subsequently contribute to the epidermal defects observed in HAI-1 knockout mice. The impact of HAI-1 deficiency on matriptase and prostasin proteolysis was, here, investigated in HaCaT human keratinocytes. Our results show that HAI-1 deficiency causes an increase in prostasin proteolysis via increased protein expression and zymogen activation. It remains unclear, however, whether HAI-1 deficiency increases "net" prostasin enzymatic activity because all of the activated prostasin was detected in complexes with HAI-2, suggesting that prostasin enzymatic activity is still under tight control in HAI-1-deficient keratinocytes. Matriptase proteolysis is, however, unexpectedly suppressed by HAI-1 deficiency, as manifested by decreases in zymogen activation, shedding of active matriptase, and matriptase-dependent prostasin zymogen activation. This suppressed proteolysis results mainly from the reduced ability of HAI-1-deficient HaCaT cells to activate matriptase and the rapid inhibition of nascent active matriptase by HAI-2 and other yet-to-be-identified protease inhibitors. Our study provides novel insights with opposite impacts by HAI-1 deficiency on matriptase versus prostasin proteolysis in keratinocytes.
    MeSH term(s) Gene Deletion ; HaCaT Cells ; Humans ; Keratinocytes/metabolism ; Proteinase Inhibitory Proteins, Secretory/deficiency ; Proteinase Inhibitory Proteins, Secretory/genetics ; Proteinase Inhibitory Proteins, Secretory/physiology ; Proteolysis ; Serine Endopeptidases/metabolism ; Skin/cytology ; Skin/metabolism
    Chemical Substances Proteinase Inhibitory Proteins, Secretory ; SPINT1 protein, human ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-) ; prostasin (EC 3.4.21.-)
    Language English
    Publishing date 2021-01-24
    Publishing country Japan
    Document type Journal Article
    ZDB-ID 1149134-6
    ISSN 1749-0774 ; 0914-7470
    ISSN (online) 1749-0774
    ISSN 0914-7470
    DOI 10.1007/s13577-021-00488-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Plasminogen-Dependent Matriptase Activation Accelerates Plasmin Generation by Differentiating Primary Human Keratinocytes.

    Chen, Ya-Wen / Yin, Shi / Lai, Ying-Jung J / Johnson, Michael D / Lin, Chen-Yong

    The Journal of investigative dermatology

    2016  Volume 136, Issue 6, Page(s) 1210–1218

    Abstract: Pericellular plasmin generation, an important pathophysiological process, can be initiated and accelerated by the autoactivation of the type 2 transmembrane serine protease matriptase and subsequent activation of urokinase plasminogen activator. The link ...

    Abstract Pericellular plasmin generation, an important pathophysiological process, can be initiated and accelerated by the autoactivation of the type 2 transmembrane serine protease matriptase and subsequent activation of urokinase plasminogen activator. The link between matriptase and plasminogen was initially thought to be one-directional: from matriptase, through plasminogen activator, to plasminogen. However, in the current study, we now show that primary human keratinocytes that are undergoing calcium-induced differentiation can rapidly activate matriptase in response to serum treatment via a mechanism dependent on intracellular calcium, protein kinase C, and phosphatidylinositol 3-kinases-based signaling. The serum factor, responsible for the induction of matriptase zymogen activation, was shown to be plasminogen. A sub-pM concentration of plasminogen (but not plasmin) acting at the cell surface is sufficient to induce matriptase activation, suggesting high potency and specificity of the induction. After matriptase zymogen activation, a proportion of active matriptase is shed into extracellular milieu and returns to the cell surface to accelerate plasmin generation. The ability of plasminogen to induce matriptase zymogen activation and the subsequent acceleration of plasmin generation by active matriptase reveals a feed-forward mechanism that allows differentiating human keratinocytes to rapidly and robustly activate pericellular proteolysis.
    MeSH term(s) Cell Membrane/metabolism ; Cells, Cultured ; Enzyme Activation/physiology ; Fibrinolysin/metabolism ; Humans ; Keratinocytes/cytology ; Keratinocytes/enzymology ; Plasminogen/metabolism ; Proteolysis ; Sampling Studies ; Sensitivity and Specificity ; Serine Endopeptidases/metabolism
    Chemical Substances Plasminogen (9001-91-6) ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase (EC 3.4.21.-) ; Fibrinolysin (EC 3.4.21.7)
    Language English
    Publishing date 2016-02-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2016.01.029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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