Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton, Justin Raymond; Trejo, JoAnn

doi:10.1146/annurev-pharmtox-011613-140016

Cited by 52 publications

(58 citation statements)

References 145 publications

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“…We propose that highly druggable GPCRs are a promising class of targets for metastatic cancer. In fact, several lines of evidence indicate that the GPCR PAR1 is an attractive therapeutic target for advanced breast cancer (11,45). PAR1 confers tumor cell motility, invasiveness, survival and self-renewal in breast cancer and other cancer types (46).…”

Section: Discussionmentioning

confidence: 99%

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The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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Aberrant G protein-coupled receptor (GPCR) expression and activation has been linked to tumor initiation, progression, invasion and metastasis. However, compared with other cancer drivers, the exploitation of GPCRs as potential therapeutic targets has been largely ignored, despite the fact that GPCRs are highly druggable. Therefore, to advance the potential status of GPCRs as therapeutic targets, it is important to understand how GPCRs function together with other cancer drivers during tumor progression. We now report that the a-arrestin domain-containing protein-3 (ARRDC3) acts as a tumor suppressor in part by controlling signaling and trafficking of the GPCR, protease-activated receptor-1 (PAR1). In a series of highly invasive basal-like breast carcinomas, we found that expression of ARRDC3 is suppressed while PAR1 is aberrantly overexpressed because of defective lysosomal sorting that results in persistent signaling. Using a lentiviral doxycycline-inducible system, we demonstrate that re-expression of ARRDC3 in invasive breast carcinoma is sufficient to restore normal PAR1 trafficking through the ALGinteracting protein X (ALIX)-dependent lysosomal degradative pathway. We also show that ARRDC3 re-expression attenuates PAR1-stimulated persistent signaling of c-Jun NH2-terminal kinase (JNK) in invasive breast cancer. Remarkably, restoration of ARRDC3 expression significantly reduced activated PAR1-induced breast carcinoma invasion, which was also dependent on JNK signaling. These findings are the first to identify a critical link between the tumor suppressor ARRDC3 and regulation of GPCR trafficking and signaling in breast cancer.G protein-coupled receptors (GPCRs) are a large family of cell surface signaling receptors that play a critical role in cancer growth and development by regulating cellular proliferation, invasion, migration, immune cell-mediated functions, angiogenesis and survival at metastatic sites (1-3). GPCR function can be altered in cancer through aberrant overexpression, gain-of-function activating mutations, mutations in downstream G protein signaling effectors, and increased production and secretion of GPCR activating ligands by both tumor cells and surrounding stromal cells (4-7). As cell surface receptors with highly druggable sites, GPCRs are the largest class of drug targets, with over 30% of current FDAhttp://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 99%

“…Several GPCRs implicated in metastatic cancer, including protease-activated receptor-1 (PAR1), have also proven to be highly druggable (10,11). PAR1 is overexpressed in invasive ductal breast carcinoma but not in normal mammary epithelial tissue (12,13).…”

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confidence: 99%

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Arakaki

Pan

Lin

et al. 2018

Journal of Biological Chemistry

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“…Apart from controlling coagulation, cellular mechanisms that render TF non‐coagulant also support TF‐FVIIa cell signaling. Coagulation proteases, including TF‐FVIIa, TF‐FVIIa‐FXa, thrombin and activated protein C (aPC), cleave the extracellular domains of PARs and elicit both heterotrimeric G protein and β‐arrestin‐coupled signaling . Although all coagulation proteases can cleave PARs with variable efficiency, protease interactions with specific receptors, their subcellular localization in microdomains, PAR heterodimerization and alternative PAR cleavages result in biased agonism and sometimes opposing downstream cellular responses.…”

Section: Tf‐fviia and Intracellular Signalingmentioning

confidence: 99%

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

125

123

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The tissue factor (TF) pathway plays a central role in hemostasis and thrombo-inflammatory diseases. Although structure-function relationships of the TF initiation complex are elucidated, new facets of the dynamic regulation of TF's activities in cells continue to emerge. Cellular pathways that render TF non-coagulant participate in signaling of distinct TF complexes with associated proteases through the protease-activated receptor (PAR) family of G protein-coupled receptors. Additional co-receptors, including the endothelial protein C receptor (EPCR) and integrins, confer signaling specificity by directing subcellular localization and trafficking. We here review how TF is switched between its role in coagulation and cell signaling through thiol-disulfide exchange reactions in the context of physiologically relevant lipid microdomains. Inflammatory mediators, including reactive oxygen species, activators of the inflammasome, and the complement cascade play pivotal roles in TF procoagulant activation on monocytes, macrophages and endothelial cells. We furthermore discuss how TF, intracellular ligands, co-receptors and associated proteases are integrated in PAR-dependent cell signaling pathways controlling innate immunity, cancer and metabolic inflammation. Knowledge of the precise interactions of TF in coagulation and cell signaling is important for understanding effects of new anticoagulants beyond thrombosis and identification of new applications of these drugs for potential additional therapeutic benefits.

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“…[1][2][3][4][5] In the vascular compartment, both PAR-1 and PAR-2 are expressed on endothelial cells (EC), smooth muscle cells, and leukocytes whereas only PAR-1 is expressed on platelets. Cell context-dependent signaling mechanisms that rely on the expression of cofactors, noncanonical cleavage, and their downstream effectors have been described.…”

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confidence: 99%

Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP)

et al. 2019

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Factor VII activating protease (FSAP) is a circulating serine protease implicated in thrombosis, atherosclerosis, stroke, and cancer. Using an overexpression strategy, we have systematically investigated the role of protease activated receptors (PAR)‐1, ‐2, ‐3, and ‐4 on FSAP‐mediated signaling in HEK293T and A549 cells. Cleavage of PAR‐reporter constructs and MAPK phosphorylation was used to monitor receptor activation. FSAP cleaved PAR‐2 and to a lesser degree PAR‐1, but not PAR‐3 or PAR‐4 in both cell types. Robust MAPK activation in response to FSAP was observed after PAR‐2, but not PAR‐1 overexpression in HEK293T. Recombinant serine protease domain of wild type FSAP, but not the Marburg I isoform of FSAP, could reproduce the effects of plasma purified FSAP. Canonical cleavage of both PARs was suggested by mass spectrometric analysis of synthetic peptide substrates from the N‐terminus of PARs and site directed mutagenesis studies. Surprisingly, knockdown of endogenous PAR‐1, but not PAR‐2, prevented the apoptosis‐inhibitory effect of FSAP, suggesting that PAR1 is nevertheless a direct or indirect target in some cell types. This molecular characterization of PAR‐1 and ‐2 as cellular receptors of FSAP will help to define the actions of FSAP in the context of cancer and vascular biology.

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Challenges and Opportunities in Protease-Activated Receptor Drug Development

Cited by 52 publications

References 145 publications

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

The α-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein–coupled receptor lysosomal sorting and signaling

Tissue factor at the crossroad of coagulation and cell signaling

Protease activated receptors (PAR)‐1 and ‐2 mediate cellular effects of factor VII activating protease (FSAP)

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