Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

Tseng, Chun-Che; Jia, Bailing; Barndt, Robert J.; Gu, Yayun; Chen, Chien‐Yu; Tseng, I-Chu; Sf, Su; Wang, Jehng-Kang; Johnson, Michael D.; Lin, Chen‐Yong

doi:10.1371/journal.pone.0183507

Cited by 33 publications

(30 citation statements)

References 60 publications

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“…After removal of the insoluble fraction by centrifugation, the protein concentration was determined, and samples containing equal amounts proteins were separated by SDS-PAGE, transferred to nitrocellulose membrane, and probed with matriptase N-terminal monoclonal antibody PS6. The generation and characterization of the mAb PS6 have been described previously [13].…”

Section: Immunoblotmentioning

confidence: 99%

“…Under physiological conditions, cell-associated active matriptase is a short-lived species due to its rapid inhibition by HAI-1 through the formation of a stable one-to-one complex [11]. A proportion of the active matriptase is, however, also rapidly shed from the surface of cells [12,13]. HAI-1 is also an integral membrane protein and so can be targeted to the basolateral plasma membrane of polarized epithelial cells [14,15].…”

Section: Introductionmentioning

confidence: 99%

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The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane

et al. 2020

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Matriptase plays important roles in epithelial integrity and function, which depend on its sorting to the basolateral surface of cells, where matriptase zymogen is converted to an active enzyme in order to act on its substrates. After activation, matriptase undergoes HAI-1-mediated inhibition, internalization, transcytosis, and secretion from the apical surface into the lumen. Matriptase is a mosaic protein with several distinct protein domains and motifs, which are a reflection of matriptase's complex cellular itinerary, life cycle, and the tight control of its enzymatic activity. While the molecular determinants for various matriptase regulatory events have been identified, the motif(s) required for translocation of human matriptase to the basolateral plasma membrane is unknown. The motif previously identified in rat matriptase is not conserved between the rodent and the primate. We, here, revisit the question for human matriptase through the use of a fusion protein containing a green fluorescent protein linked to the matriptase N-terminal fragment ending at Gly-149. A conserved seven amino acid motif EEGEVFL, which is similar to the monoleucine C-terminal to an acidic cluster motif involved in the basolateral targeting for some growth factors, has been shown to be required for matriptase translocation to the basolateral plasma membrane of polarized MDCK cells. Furthermore, time-lapse video microscopy showed that the motif appears to be required for entry into the correct transport vesicles, by which matriptase can undergo rapid trafficking and translocate to the plasma membrane. Our study reveals that the EEGEVFL motif is necessary, but may not be sufficient, for matriptase basolateral membrane targeting and serves as the basis for further research on its pathophysiological roles.

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Section: Immunoblotmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane

et al. 2020

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“…Matriptase shedding requires proteolytic cleavage distinct from but tightly coupled with its maturation cleavages . In general, shedding from cell membrane increases the duration of matriptase activation and the accessibility of matriptase to its substrates.…”

Section: Discussionmentioning

confidence: 99%

“…In general, shedding from cell membrane increases the duration of matriptase activation and the accessibility of matriptase to its substrates. The shed matriptase contains the catalytic ectodomain and in tumour microenvironment may more readily activate oncogenic substrates and change the ECM contributing to tumour progression . 3‐Cl‐AHPC also induces matriptase shedding (Figure B), but it is not certain whether 3‐Cl‐AHPC‐induced matriptase/HAI‐1 complex formation and shedding are correlative or not.…”

Section: Discussionmentioning

confidence: 99%

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

Chen

Liu

et al. 2018

J Cellular Molecular Medi

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Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules.

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“…We already showed that PMA-and TGF-induced Prss14/epithin shedding depends on TACE (15,16). Although Prss14/epithin shedding can be blocked by serine protease inhibitors such as ecotin (17,28), we still believe that shedding is mediated by TACE, as tested by specific inhibition and knockdown experiments (Figs. 1D and E).…”

Section: Jnk Inhibition In Addition To Pma Can Mediate Prss14/epithinmentioning

confidence: 93%

A JUN N-terminal kinase inhibitor induces ectodomain shedding of the cancer-associated membrane protease Prss14/epithin via protein kinase CβII

Yoon

Cho

Kim

et al. 2020

Journal of Biological Chemistry

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Serine protease 14 (Prss14)/epithin is a transmembrane serine protease that plays essential roles in tumor progression and metastasis and therefore is a promising target for managing cancer. Prss14/epithin shedding may underlie its activity in cancer and worsen outcomes; accordingly, a detailed understanding of the molecular mechanisms in Prss14/epithin shedding may inform the design of future cancer therapies. On the basis of our previous observation that an activator of PKC, phorbol 12-myristate 13-acetate (PMA), induces Prss14/epithin shedding, here we further investigated the intracellular signaling pathway involved in this process. While using mitogen-activated protein kinase inhibitors to investigate possible effectors of downstream PKC signaling, we unexpectedly found that an inhibitor of c-Jun N-terminal kinase (JNK), SP600125, induces Prss14/epithin shedding even in the absence of PMA. SP600125-induced shedding, like that stimulated by PMA, was mediated by tumor necrosis factor-α–converting enzyme. In contrast, a JNK activator, anisomycin, partially abolished the effects of SP600125 on Prss14/epithin shedding. Moreover, the results from loss-of-function experiments with specific inhibitors, short hairpin RNA–mediated knockdown, and overexpression of dominant-negative PKCβII variants indicated that PKCβII is a major player in JNK inhibition– and PMA-mediated Prss14/epithin shedding. SP600125 increased phosphorylation of PKCβII and tumor necrosis factor-α–converting enzyme and induced their translocation into the plasma membrane. Finally, in vitro cell invasion experiments and bioinformatics analysis of data in The Cancer Genome Atlas breast cancer database revealed that JNK and PKCβII are important for Prss14/epithin-mediated cancer progression. These results provide important information regarding strategies against tumor metastasis.

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Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity

Cited by 33 publications

References 60 publications

The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane

The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

A JUN N-terminal kinase inhibitor induces ectodomain shedding of the cancer-associated membrane protease Prss14/epithin via protein kinase CβII

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