Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer

Arora, Puneeta; Ricks, Tiffany K.; Trejo, JoAnn

doi:10.1242/jcs.03409

Cited by 129 publications

(124 citation statements)

References 87 publications

(85 reference statements)

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“…66 and reviewed in Refs. 3,67). Recently, it was reported that TLR4 activation results in sequential utilization of MyD88-and TRIF-dependent signaling (68).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

135

149

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Proteinase-activated receptor 2 (PAR 2 ), a seven-transmembrane G protein-coupled receptor, is activated at inflammatory sites by proteolytic cleavage of its extracellular N terminus by trypsin-like enzymes, exposing a tethered, receptor-activating ligand. Synthetic agonist peptides (AP) that share the tethered ligand sequence also activate PAR 2 , often measured by Ca 2؉ release. PAR 2 contributes to inflammation through activation of NF-B-regulated genes; however, the mechanism by which this occurs is unknown. Overexpression of human PAR 2 in HEK293T cells resulted in concentration-dependent, PAR 2 AP-inducible NF-B reporter activation that was protein synthesis-independent, yet blocked by inhibitors that uncouple G i proteins or sequester intracellular Ca 2؉ . Because previous studies described synergistic PAR 2 -and TLR4-mediated cytokine production, we hypothesized that PAR 2 and TLR4 might interact at the level of signaling. In the absence of TLR4, PAR 2 -induced NF-B activity was inhibited by dominant negative (DN)-TRIF or DN-TRAM constructs, but not by DN-MyD88, findings confirmed using cell-permeable, adapter-specific BB loop blocking peptides. Co-expression of TLR4/MD-2/CD14 with PAR 2 in HEK293T cells led to a synergistic increase in AP-induced NF-B signaling that was MyD88-dependent and required a functional TLR4, despite the fact that AP exhibited no TLR4 agonist activity. Co-immunoprecipitation of PAR 2 and TLR4 revealed a physical association that was AP-dependent. The response to AP or lipopolysaccharide was significantly diminished in TLR4 ؊/؊ and PAR 2 ؊/؊ macrophages, respectively, and SW620 colonic epithelial cells exhibited synergistic responses to co-stimulation with AP and lipopolysaccharide. Our data suggest a unique interaction between two distinct innate immune response receptors and support a novel paradigm of receptor cooperativity in inflammatory responses.

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“…66 and reviewed in Refs. 3,67). Recently, it was reported that TLR4 activation results in sequential utilization of MyD88-and TRIF-dependent signaling (68).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Rallabhandi

Nhu

Toshchakov

et al. 2008

Journal of Biological Chemistry

135

149

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“…Post-translational modification by proteolytic cleavage has been recognized as an important mechanism for the functional modulation of a diverse array of cell surface proteins, such as Notch, protease-activated receptors (PARs) and many cell adhesion molecules [1][2][3]. Proteolytic modification of these molecules usually takes place in the secretory pathway or on the cell surface, mediated by proprotein convertases or sheddases such as furin, MMPs and ADAMs [4].…”

Section: Introductionmentioning

confidence: 99%

Site‐specific N‐glycosylation regulates the GPS auto‐proteolysis of CD97

et al. 2009

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a b s t r a c tAuto-proteolysis at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is a hallmark of adhesion-GPCRs. Although defects in GPS auto-proteolysis have been linked to genetic disorders, information on its regulation remains elusive. Here, we investigated the GPS proteolysis of CD97, a human leukocyte-restricted and tumor-associated adhesion-GPCR. We found that CD97 is incompletely processed, unlike its close homolog, epidermal growth factor-like module-containing mucin-like hormone receptor 2. A unique pattern of N-glycosylation within the GPS motif of related adhesion-GPCRs was identified. The use of N-glycosylation inhibitors and mutants confirm site-specific N-glycosylation is an important determinant of GPS proteolysis in CD97. Our results suggest that N-glycosylation may regulate the processing of adhesion-GPCRs leading to the production of either cleaved or uncleaved molecules.

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“…PAR1, PAR3 and PAR4 are activated by thrombin whereas PAR2 is a receptor for trypsin (1). In addition to thrombin, PAR-1 is also cleaved and activated by plasmin, activated protein C (APC), factor Xa, factor VIIa and the matrix metalloprotease MMP-1 (2). Once activated PARs couple to heterotrimeric G-proteins.…”

Section: Introductionmentioning

confidence: 99%

Protease-activated receptor-1 regulates cytokine production and induces the suppressor of cytokine signaling-3 in microglia

Fabrizi¹

2009

Int J Mol Med

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Abstract. Protease-activated receptors (PARs) are cleaved and activated by thrombin and other extracellular proteases which are released during tissue trauma and inflammation. PAR-1 is the prototypic member of the PAR family and has been shown to be upregulated in several brain pathologies being expressed by neurons and glial cells. The present experiments show that the administration of the PAR-1 activating peptides (TRAP6 and TFLLR) inhibits the production of the pro-inflammatory cytokines TNF-· and IL-6 in microglial cells treated with lipopolysaccharide (LPS) while promoting the release of the anti-inflammatory cytokine IL-10. Conversely, the addition of the specific PAR-2 agonist SLIGRL had no effect on the amount of cytokines released following LPS treatment. Consistent with these data PAR-1, but not PAR-2, stimulation upregulates the expression of the suppressor of cytokine signaling-3 (SOCS-3). The present data support the hypothesis that in microglia PAR-1 may be involved in the regulation of inflammatory reactions modulating the balance between pro-and anti-inflammatory cytokines possibly through SOCS induction.

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Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer

Cited by 129 publications

References 87 publications

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Analysis of Proteinase-activated Receptor 2 and TLR4 Signal Transduction

Site‐specific N‐glycosylation regulates the GPS auto‐proteolysis of CD97

Protease-activated receptor-1 regulates cytokine production and induces the suppressor of cytokine signaling-3 in microglia

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