Proteolytic Activation of the Protease-activated Receptor (PAR)-2 by the Glycosylphosphatidylinositol-anchored Serine Protease Testisin

Driesbaugh, Kathryn H.; Buzza, Marguerite S.; Martin, Erik W.; Conway, Gregory D.; Kao, Joseph P. Y.; Antalis, Toni M.

doi:10.1074/jbc.m114.628560

Cited by 31 publications

(29 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…46 To address this possibility and to further establish the capacity of pro-matriptase to support activation of PAR2 by coagulation proteases, we reconstituted the theoretical signaling cascade in HeLa and KOLF cells, which express little if any endogenous matriptase, prostasin, or hepsin ( Figure 1C). Consistent with direct activation of matriptase, coexpression of wild-type matriptase zymogen, but neither catalytically inactive pro-matriptase nor proforms of prostasin, hepsin, or testisin/Prss21 (another MASP with PAR2 processing activity 55 ), facilitated FVIIa-and prostasin-induced cleavage of PAR2 and FVIIa-, FXa-, and prostasin-mediated cleavage of PAR2 G35K in HeLa and KOLF cells ( Figure 3E; supplemental Figure 6). …”

Section: Resultsmentioning

confidence: 53%

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Gall

Szabo

Lee

et al. 2016

Blood

View full text Add to dashboard Cite

The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation.

show abstract

Section: Resultsmentioning

confidence: 53%

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Gall

Szabo

Lee

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…PAR2 is also known to induce cAMP levels by coupling to Gas (Driesbaugh et al, 2015; Scott et al, 2003). cAMP opposes the rise in intracellular Ca 2+ (Chabardè s et al, 1999; Chow and Davis, 2000).…”

Section: Resultsmentioning

confidence: 99%

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

et al. 2019

View full text Add to dashboard Cite

SUMMARY Alveolar macrophages (AMs), upon sensing pathogens, trigger host defense by activating toll-like receptor 4 (TLR4), but the counterbalancing mechanisms that deactivate AM inflammatory signaling and prevent lethal edema, the hallmark of acute lung injury (ALI), remain unknown. Here, we demonstrate the essential role of AM protease-activating receptor 2 (PAR2) in rapidly suppressing inflammation to prevent long-lasting injury. We show that thrombin, released during TLR4-induced lung injury, directly activates PAR2 to generate cAMP, which abolishes Ca2+ entry through the TRPV4 channel. Deletion of PAR2 and thus the accompanying cAMP generation augments Ca2+ entry via TRPV4, causing sustained activation of the transcription factor NFAT to produce long-lasting TLR4-mediated inflammatory lung injury. Rescuing thrombin-sensitive PAR2 expression or blocking TRPV4 activity in PAR2-null AMs restores their capacity to resolve inflammation and reverse lung injury. Thus, activation of the thrombin-induced PAR2-cAMP cascade in AMs suppresses TLR4 inflammatory signaling to reinstate tissue integrity.

show abstract

“…ERK1 and ERK2 are protein kinases with dual specificity that participate in the MAPK cascade controlling cell growth and differentiation, while PD98059 has been shown to act as a highly selective inhibitor of MEK1 activation in vivo [20][21][22]. Next, we assessed the effect of U0126, a synthetic organic compound (1,4-diamino-2,3-dicyano-1,4-bis [2-aminophenylthio] butadiene) that is a highly selective inhibitor of ERK 1 and ERK2.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of interleukin-13 production by granulocyte-macrophage colony-stimulating factor-dependent macrophages via protease-activated receptor-2

Yamaguchi

Yamamoto

Sakamoto

et al. 2015

Blood Cells, Molecules, and Diseases

View full text Add to dashboard Cite

Proteolytic Activation of the Protease-activated Receptor (PAR)-2 by the Glycosylphosphatidylinositol-anchored Serine Protease Testisin

Cited by 31 publications

References 60 publications

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

Matriptase activation connects tissue factor–dependent coagulation initiation to epithelial proteolysis and signaling

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

Mechanism of interleukin-13 production by granulocyte-macrophage colony-stimulating factor-dependent macrophages via protease-activated receptor-2

Contact Info

Product

Resources

About