Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_0E5AF1E2F893
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation.
Périodique
Plos Genetics
Auteur(s)
Szabo R., Uzzun Sales K., Kosa P., Shylo N.A., Godiksen S., Hansen K.K., Friis S., Gutkind J.S., Vogel L.K., Hummler E., Camerer E., Bugge T.H.
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Statut éditorial
Publié
Date de publication
2012
Peer-reviewed
Oui
Volume
8
Numéro
8
Pages
e1002937
Langue
anglais
Notes
Publication types: Journal Article
Résumé
Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/10/2012 19:29
Dernière modification de la notice
20/08/2019 13:35
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