Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Ramachandran, Rithwik; Altier, Christophe; Οικονομοπούλου, Κατερίνα; Hollenberg, Morley D.

doi:10.1124/pr.115.010991

Cited by 56 publications

(74 citation statements)

References 356 publications

(390 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Coagulation proteases signal through G-protein coupled protease activated receptors (PAR) in a cell-specific manner4,27. In podocytes, but not in glomerular endothelial or tubular cells, aPC’s cytoprotective effect requires PAR35,28. Congruently, aPC failed to promote nuclear translocation of sXBP1 in PAR3 knockdown podocytes establishing that PAR3 is required for aPC mediated UPR reprogramming in podocytes (Supplemental Figure 6A).…”

Section: Resultsmentioning

confidence: 98%

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Madhusudhan

Wang

Ghosh

et al. 2017

Blood

View full text Add to dashboard Cite

Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling both impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER)-homeostasis. Analogous to insulin, physiological levels of aPC maintain endoplasmic reticulum (ER) proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER-response, while genetic or pharmacological restoration of aPC maintains ER-proteostasis in DKD models. Importantly, in mice with podocyte specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85β. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant UPR target genes are involved in maintenance of ER-proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to re-configure ER-signaling and restore proteostasis. These results identify ER-reprogramming as a novel hormone-like function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.

show abstract

Section: Resultsmentioning

confidence: 98%

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Madhusudhan

Wang

Ghosh

et al. 2017

Blood

View full text Add to dashboard Cite

show abstract

“…Interestingly, it was recently shown that the biological activities of these proteinases can be mediated through specific proteinase-activated receptor (PAR) activation. PARs are members of the G-protein-coupled family, seven-transmembrane domain receptors, and their activation occurs through proteolytic cleavage of the N-terminal domain by proteinases, leading to the generation of a new N-terminal “tethered ligand,” which binds to the receptor itself resulting in its autoactivation [1, 2]. Until now, four members of the PAR family were discovered: PAR 1 , PAR 3 , and PAR 4 which are activated by thrombin and PAR 2 that can be activated by trypsin, neutrophil proteinase 3, tissue factor/factor VIIa/factor Xa, mast cell tryptase, membrane-tethered serine proteinase-1, or gingipains [3, 4].…”

Section: Introductionmentioning

confidence: 99%

“…Although the structures and mechanisms related to the activation of these receptors are similar, they can be expressed by different cells; hence, in each cell, their activation may lead to distinct roles in pathophysiological processes, such as growth, development, inflammation, tissue repair, and pain [2, 7–10]. PAR 1 is expressed by platelets, osteoblast endothelial cells, epithelial cells, fibroblasts, myocytes, neurons, and astrocytes, and it seems to play an important role in injured tissues.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of Proteinase-Activated Receptors 1 and 2 in the Regulation of Periodontal Tissue Metabolism and Disease

Rovai

Holzhausen

2017

Journal of Immunology Research

View full text Add to dashboard Cite

Proteinase-activated receptors 1 (PAR1) and 2 (PAR2) are the most highly expressed members of the PAR family in the periodontium. These receptors regulate periodontal inflammatory and repair processes through their activation by endogenous and bacterial enzymes. PAR1 is expressed by the periodontal cells such as human gingival fibroblasts, gingival epithelial cells, periodontal ligament cells, osteoblasts, and monocytic cells and can be activated by thrombin, matrix metalloproteinase 1 (MMP-1), MMP-13, fibrin, and gingipains from Porphyromonas gingivalis. PAR2 is expressed by neutrophils, osteoblasts, oral epithelial cells, and human gingival fibroblasts, and its possible activators in the periodontium are gingipains, neutrophil proteinase 3, and mast cell tryptase. The mechanisms through which PARs can respond to periodontal enzymes and result in appropriate immune responses have until recently been poorly understood. This review discusses recent findings that are beginning to identify a cardinal role for PAR1 and PAR2 on periodontal tissue metabolism.

show abstract

“…2-furoyl-LIGRLO-NH 2 (2fLIGRLO) and SLIGRL-NH 2 . [11][12][13] A recent paper suggests that thrombin could activate PAR2 in situations, where high levels of active thrombin can be generated, such as in a tumor microenvironment or in the setting of acute tissue trauma. 14) Also, inflammatory stimuli, such as interleukin-1α and tumor necrosis factor-α, 15) can induce expression of PAR2 in the endothelium, which can lead * To whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

Progression of Time-Dependent Changes to the Mechanisms of Vasodilation by Protease-Activated Receptor 2 in Metabolic Syndrome

Maruyama

McGuire

Kagota

2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by serine proteases released from tissues or by synthetic peptide ligands administered pharmacologically. Its wide expression in the cardiovascular system, particularly within the endothelium, vasodilation activity, and link to increased expression of inflammatory cytokines positions PAR2 as a potentially important regulator of vascular pathology under conditions of tissue inflammation, and injury; and thus, a pharmaceutical target for new therapeutics. Obesity is considered a chronic low-grade systemic inflammatory condition as inflammatory cytokines released from adipocytes are closely related to development of metabolic syndrome and related disorders. Our work over the past five-years has focused on the changes in vasomotor functions of PAR2 in metabolic syndrome, using an animal model known as the SHRSP.Z-Lepr fa /IzmDmcr rats (SHRSP.ZF). In young SHRSP.ZF that had already developed impaired responses to nitric oxide, we reported that PAR2-induced endothelium-dependent vasodilation is preserved. However, this PAR2 vasodilation decreased with increasing age and further chronic exposure to the conditions of metabolism disorder. These findings raise the possibility that PAR2 regulates tissue perfusion and can protect organs from injury, which is an increasing clinical concern at later stages of metabolic syndrome. Here we present our studies on the time-dependent changes in vasoreactivity to PAR2 in metabolic syndrome and the underlying mechanisms. Furthermore, we discuss the implications of these age-related changes in PAR2 for the cardiovascular system in metabolic syndrome.

show abstract

Proteinases, Their Extracellular Targets, and Inflammatory Signaling

Cited by 56 publications

References 356 publications

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

The Role of Proteinase-Activated Receptors 1 and 2 in the Regulation of Periodontal Tissue Metabolism and Disease

Progression of Time-Dependent Changes to the Mechanisms of Vasodilation by Protease-Activated Receptor 2 in Metabolic Syndrome

Contact Info

Product

Resources

About