G-protein coupled receptor agonists mediate Neu1 sialidase and matrix metalloproteinase-9 cross-talk to induce transactivation of TOLL-like receptors and cellular signaling

Abdulkhalek, Samar; Guo, Merry; Amith, Schammim Ray; Jayanth, Preethi; Szewczuk, Myron R.

doi:10.1016/j.cellsig.2012.06.016

Cited by 49 publications

(66 citation statements)

References 37 publications

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“…A cross-talk between TLR and GPCR has been described, which is essential for cellular signaling in the absence of TLR natural ligands. This cross-talk is basically a molecular organizational GPCR signaling platform that promotes the transactivation of TLR, through potentiation of Neuraminidase 1 and matrix metalloproteinase-9 at the cell surface [93]. Intriguingly, LPC derived from the human pathogen Schistosoma mansoni activates TLR-2-dependent signaling involved in eosinophil activation and recruitment, probably through cross-talk to a GPCR [94].…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Analysis of a Platelet-Activating Lysophosphatidylcholine of Trypanosoma cruzi

et al. 2014

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Background Trypanosoma cruzi is the causative agent of the life-threatening Chagas disease, in which increased platelet aggregation related to myocarditis is observed. Platelet-activating factor (PAF) is a potent intercellular lipid mediator and second messenger that exerts its activity through a PAF-specific receptor (PAFR). Previous data from our group suggested that T. cruzi synthesizes a phospholipid with PAF-like activity. The structure of T. cruzi PAF-like molecule, however, remains elusive.Methodology/Principal findingsHere, we have purified and structurally characterized the putative T. cruzi PAF-like molecule by electrospray ionization-tandem mass spectrometry (ESI-MS/MS). Our ESI-MS/MS data demonstrated that the T. cruzi PAF-like molecule is actually a lysophosphatidylcholine (LPC), namely sn-1 C18:1(delta 9)-LPC. Similar to PAF, the platelet-aggregating activity of C18:1-LPC was abrogated by the PAFR antagonist, WEB 2086. Other major LPC species, i.e., C16:0-, C18:0-, and C18:2-LPC, were also characterized in all T. cruzi stages. These LPC species, however, failed to induce platelet aggregation. Quantification of T. cruzi LPC species by ESI-MS revealed that intracellular amastigote and trypomastigote forms have much higher levels of C18:1-LPC than epimastigote and metacyclic trypomastigote forms. C18:1-LPC was also found to be secreted by the parasite in extracellular vesicles (EV) and an EV-free fraction. A three-dimensional model of PAFR was constructed and a molecular docking study was performed to predict the interactions between the PAFR model and PAF, and each LPC species. Molecular docking data suggested that, contrary to other LPC species analyzed, C18:1-LPC is predicted to interact with the PAFR model in a fashion similar to PAF.Conclusions/SignificanceTaken together, our data indicate that T. cruzi synthesizes a bioactive C18:1-LPC, which aggregates platelets via PAFR. We propose that C18:1-LPC might be an important lipid mediator in the progression of Chagas disease and its biosynthesis could eventually be exploited as a potential target for new therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Analysis of a Platelet-Activating Lysophosphatidylcholine of Trypanosoma cruzi

et al. 2014

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“…It is well known that agonist-induced GPCRs have been shown to activate numerous MMPs [75], including MMP-3 [76], MMP-2 and MMP9 [77, 78], including members of the ADAM family of metalloproteinases [79, 80]. We have shown that GPCR agonists can directly activate Neu1 through the intermediate activity of MMP9 in order to induce transactivation of TLRs and subsequent cellular signaling [62, 65]. These findings are consistent with our GPCR-Neu1-MMP9 signaling axis tethered to glycosylated receptors such as EGFR, Trk, insulin, cell surface and intracellular TLRs.…”

Section: A Novel Egfr-signaling Platform and Its Targeted Translationmentioning

confidence: 99%

“…MMP9 and neuromedin B GPCR (NMBR) are associated with each other on the cell surface, and together form a complex with EGFR [30], TrkA receptors [35], insulin receptor IRβ subunits [59], TLR-4 [34, 61, 62, 64], and TLR7 and −9 [65]. Co-immunoprecipitation experiments using cell lysates from RAW-blue macrophage cells demonstrated that the 80 kDa NMBR isoform forms a complex with the active 88 kDa MMP9 isoform from naïve or lipopolysaccharide (LPS)-stimulated cells [62]. These data further validated that NMBR forms a complex with MMP9 on the cell surface of naïve cells.…”

Section: Gpcr Signal Integration In Receptor Tyrosine Kinase Activationmentioning

confidence: 99%

“…These data further validated that NMBR forms a complex with MMP9 on the cell surface of naïve cells. The report also showed that GPCR agonists (including bombesin, lysophosphatidic acid (LPA), cholesterol, angiotensin-1 and −2, and bradykinin) binding to their respective GPCRs induce Neu1 activity within 1 minute [62]. This prompt Neu1 activity was blocked by Gα i -sensitive pertussis toxin, the neuraminidase inhibitor oseltamivir phosphate, broad-range MMP inhibitors galardin and piperazine, anti-Neu1 and anti-MMP9 antibodies, and siRNA knockdown of MMP9.…”

Section: Gpcr Signal Integration In Receptor Tyrosine Kinase Activationmentioning

confidence: 99%

“…In addition, the activation of NF-κB in macrophages can be mediated by cell surface and intracellular Toll-like receptors (TLR) [183–186, 188], the process of which has been shown to play major roles in cancer. We have reported for the first time that Neu1 sialidase clearly plays a central role in mediating cell surface and nucleic acid-induced intracellular TLR activation, and the interactions involving NMBR–MMP9–Neu1 cross-talk constitute a novel intracellular TLR signaling platform that is essential for NF-κB activation and pro-inflammatory responses [31, 61, 62, 65]. …”

Section: Immune-mediated Tumorigenesis and The Role Of Macrophagesmentioning

confidence: 99%

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Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

2016

Self Cite

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Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.

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Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway

Zhang

Chen

Zhen

et al. 2017

Journal Cellular Physiology

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Annexin A2 (AnxA2) has been shown to play multiple roles in growth, development, and metabolism, but the functions of AnxA2 and the signaling pathways associated with AnxA2 are still not fully understood. In this study, we aim to reveal whether and how AnxA2 could be involved in milk synthesis and proliferation of bovine mammary epithelial cells (BMECs). Using gene function study approaches, we found that AnxA2 positively regulates PIP3 level, phosphorylation of mTOR, and protein levels of SREBP-1c and Cyclin D1 leading to milk synthesis and cell proliferation. We further observed that both AnxA2-36 kD phosphorylated form and AnxA2-33 kD protein could be induced from AnxA2-36 kD protein in BMECs under methionine, leucine, estrogen or prolactin stimulation. These above results strongly demonstrate that AnxA2 functions as a critical regulator for amino acid or hormone-induced milk synthesis and cell proliferation via the PI3K-mTOR-SREBP-1c/Cyclin D1 signaling pathway.

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G-protein coupled receptor agonists mediate Neu1 sialidase and matrix metalloproteinase-9 cross-talk to induce transactivation of TOLL-like receptors and cellular signaling

Cited by 49 publications

References 37 publications

Structural and Functional Analysis of a Platelet-Activating Lysophosphatidylcholine of Trypanosoma cruzi

Structural and Functional Analysis of a Platelet-Activating Lysophosphatidylcholine of Trypanosoma cruzi

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway

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