Lysophosphatidic Acid Receptor 5 Inhibits B Cell Antigen Receptor Signaling and Antibody Response

Hu, Jiancheng; Oda, Shannon K.; Shotts, Kristin M.; Donovan, Erin; Strauch, Pamela; Pujanauski, Lindsey M.; Victorino, Francisco; Al-Shami, Amin; Fujiwara, Yuko; Tigyi, Gábor; Oravecz, Tamás; Pelanda, Roberta; Torres, Raul M.

doi:10.4049/jimmunol.1300429

Cited by 36 publications

(59 citation statements)

References 65 publications

(103 reference statements)

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“…The pro‐inflammatory responses induced by LPA in microglia, e.g., expression of pro‐inflammatory M1‐type markers and secretion of pro‐inflammatory cytokines, were attenuated by an LPA 5 inhibitor . Inhibition of B‐cell receptor signaling was observed following activation of LPA 5 in murine B cells . In the present study expression of LPA 5 and LPA 6 was down‐regulated by LPS in all the cells tested.…”

Section: Discussionsupporting

confidence: 55%

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

Ciesielska

Hromada-Judycka

Ziemlińska

et al. 2019

Journal of Leukocyte Biology

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Bacterial LPS strongly induces pro-inflammatory responses of M s after binding to CD14 protein and the TLR4/MD-2 receptor complex. The LPS-triggered signaling can be modulated by extracellular lysophosphatidic acid (LPA), which is of substantial importance for M functioning under specific pathophysiological conditions, such as atherosclerosis. The molecular mechanisms of the crosstalk between the LPS-and LPA-induced signaling, and the LPA receptors involved, are poorly known. In this report, we show that LPA strongly inhibits the LPS-induced TNF-production at the mRNA and protein levels in primary M s and M -like J774 cells. The decreased TNF-production in LPA/LPS-stimulated cells is to high extent independent of NF-B but is preceded by enhanced expression and secretion of the anti-inflammatory cytokine IL-10. The IL-10 elevation and TNFreduction are both abrogated upon depletion of the LPA 5 and LPA 6 receptors in J774 cells and can be linked with LPA-mediated activation of p38. We propose that the binding of LPA to LPA 5 and LPA 6 fine-tunes the LPS-induced inflammatory response by activating p38, and up-regulating IL-10 and down-regulating TNF-production. K E Y W O R D SCD14, inflammatory response, LPA receptor, TLR4

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Section: Discussionsupporting

confidence: 55%

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

Ciesielska

Hromada-Judycka

Ziemlińska

et al. 2019

Journal of Leukocyte Biology

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“…All cancer cell lines were maintained in Dulbecco's modified Eagle's medium with 10% fetal bovine serum (Hyclone). The AMPKα knockdown H1299 cell lines were constructed by lentiviral transduction as described before ( 36 – 38 ). For exogenous expression, 293T cells were transfected with the appropriate plasmids using the Biotool transfection reagent by following the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking phospho–Ser-621 in the C terminus of CRAF

Yuan

Yap

et al. 2018

Journal of Biological Chemistry

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The dimerization-driven paradoxical activation of RAF proto-oncogene Ser/Thr kinase (RAF) is the predominant cause of drug resistance and toxicity in cancer therapies with RAF inhibitors. The scaffold protein 14-3-3, which binds to the RAF C terminus, is essential for RAF activation under physiological conditions, but the molecular basis is unclear. Here we investigated whether and how 14-3-3 regulates the dimerization-driven transactivation of the RAF isoform CRAF by RAF inhibitors and affects drug resistance and toxicity by virtue of the dominant role of CRAF in these processes. We demonstrated that 14-3-3 enhances the dimerization-driven transactivation of CRAF by stabilizing CRAF dimers. Further, we identified AMP-activated protein kinase (AMPK) and CRAF itself as two putative kinases that redundantly phosphorylate CRAF's C terminus and thereby control its association with 14-3-3. Next, we determined whether the combinatory inhibition of AMPK and CRAF could overcome the paradoxical effect of RAF inhibitors. We found that the AMPK inhibitor (AMPKi) not only blocked the RAF inhibitor–driven paradoxical activation of ERK signaling and cellular overgrowth in Ras-mutated cancer cells by blocking phosphorylation of Ser-621 in CRAF but also reduced the formation of drug-resistant clones of BRAFV600E-mutated cancer cells. Last, we investigated whether 14-3-3 binding to the C terminus of CRAF is required for CRAF catalytic activity and observed that it was dispensable in vivo. Altogether, our study unravels the molecular mechanism by which 14-3-3 regulates dimerization-driven RAF activation and identified AMPKi as a potential agent to counteract drug resistance and adverse effects of RAF inhibitors in cancer therapies.

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“…Kinase reaction was stopped by adding 5μl per sample 5XLaemmli sample buffer. Immunoblotting was carried out as described before (36). All blots were quantified by using Image J and the graphs were generated by using GraphPad Prism 6.…”

Section: Immunoprecipitation In Vitro Kinase Assay and Western Blotmentioning

confidence: 99%

AMPKi overcomes the paradoxical activation of CRAF driven by RAF inhibitors through blocking the 14-3-3 binding to its carboxyl-terminus

Yuan

Yap

et al. 2018

Preprint

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The paradoxical activation of RAF kinase is the predominant challenge in cancer therapies with RAF inhibitors. The inhibitor-bound RAF molecules are able to transactivate their wild-type binding partners. 14-3-3 that binds to the carboxyl-terminus of RAF kinase has been suggested to regulate the dimer-dependent activation of RAF kinase under physiological conditions, though the molecular basis is not clear. In this study, we investigated the role of 14-3-3 in the paradoxical effect of RAF inhibitors. Firstly, we found that the 14-3-3 binding to the carboxyl-terminus of CRAF was essential for its transactivation. Further, we demonstrated that this binding enhanced the dimer affinity of CRAF. Since 14-3-3 binds to the phosphorylated motif, we next investigated and identified AMPK and CRAF itself as two putative kinases that phosphorylate redundantly the 14-3-3 binding motif of CRAF. Among RAF isoforms, CRAF plays a dominant role in the paradoxical effect of RAF inhibitors, and we thus determined whether the combinatory inhibition of AMPK and CRAF would block this effect. Indeed, our data showed that AMPKi not only blocked the RAF inhibitor-driven paradoxical activation of RAF signaling and cellular overgrowth in Ras-mutated cancer cells but also reduced the drug-resistant clones derived from BRAF(V600E)-mutated cancer cells. Finally, we showed that the 14-3-3 binding to the carboxyl-terminus of CRAF was dispensable for its catalytic function in vivo. Together, our study unraveled how 14-3-3 regulates the dimerization-driven RAF activation and identified AMPKi as a potential method to relieve the drug resistance and side effect of RAF inhibitors in cancer therapy.

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Lysophosphatidic Acid Receptor 5 Inhibits B Cell Antigen Receptor Signaling and Antibody Response

Cited by 36 publications

References 65 publications

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking phospho–Ser-621 in the C terminus of CRAF

AMPKi overcomes the paradoxical activation of CRAF driven by RAF inhibitors through blocking the 14-3-3 binding to its carboxyl-terminus

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