Lysophospholipid receptor activation of RhoA and lipid signaling pathways

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

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Large-scale proteomic analysis of tyrosine-phosphorylation induced by T-cell receptor or B-cell receptor activation reveals new signaling pathways

PROTEOMICS ◽

10.1002/pmic.200900011 ◽

2009 ◽

Vol 9 (13) ◽

pp. 3549-3563 ◽

Cited By ~ 39

Author(s):

Masaki Matsumoto ◽

Koji Oyamada ◽

Hidehisa Takahashi ◽

Takamichi Sato ◽

Shigetsugu Hatakeyama ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Signaling Pathways ◽

Tyrosine Phosphorylation ◽

T Cell Receptor ◽

Proteomic Analysis ◽

Large Scale ◽

Cell Receptor ◽

Receptor Activation ◽

B Cell Receptor

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Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽

10.3390/cells9020513 ◽

2020 ◽

Vol 9 (2) ◽

pp. 513 ◽

Cited By ~ 1

Author(s):

Marina Leite ◽

Miguel S. Marques ◽

Joana Melo ◽

Marta T. Pinto ◽

Bruno Cavadas ◽

...

Keyword(s):

Helicobacter Pylori ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Receptor Tyrosine Kinase ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Receptor Activation ◽

Degradation Pathway ◽

Mrna Levels ◽

H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

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Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines

Asian Pacific Journal of Cancer Prevention ◽

10.7314/apjcp.2014.15.7.3219 ◽

2014 ◽

Vol 15 (7) ◽

pp. 3219-3226 ◽

Cited By ~ 13

Author(s):

Yu Zhu ◽

Xing-Jun Liu ◽

Ping Yang ◽

Meng Zhao ◽

Li-Xia Lv ◽

...

Keyword(s):

Signaling Pathways ◽

Cell Lines ◽

Carcinoma Cell ◽

Chemotherapy Resistance ◽

Lipid Signaling ◽

Hepatic Carcinoma ◽

Carcinoma Cell Lines

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Abstract 095: Human (Pro)renin Receptor Activation Induces an Angiotensin II-Independent Pressor Response Mediated by NADPH Oxidase 4 Activity

Hypertension ◽

10.1161/hyp.66.suppl_1.095 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Michelle N Sullivan ◽

Wencheng Li ◽

Curt D Sigmund ◽

Yumei Feng

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Signaling Pathways ◽

Pressor Response ◽

Receptor Activation ◽

Fold Change ◽

Mrna Levels ◽

Ang Ii ◽

Proteolytic Activation ◽

Nadph Oxidase 4

The binding of prorenin to the (pro)renin receptor (PRR) induces non-proteolytic activation of prorenin and generation of angiotensin II (Ang II). PRR activation can also induce Ang II-independent signaling pathways. However, whether Ang II-independent signaling pathways are critical for blood pressure (BP) regulation is not known. To address this question, we created transgenic mice that overexpress the human PRR (hPRR) selectively in neurons (Syn-hPRR). Activated human prorenin (hPRO) cannot cleave endogenous mouse angiotensinogen to generate Ang II. Therefore, administration of hPRO to Syn-hPRR mice can be used to examine Ang II-independent PRR signaling in BP regulation. Intracerebroventricular (ICV) infusion of hPRO increases BP in Syn-hPRR mice (ΔMAP 23 ± 4.6, n = 4) but has no effect on wildtype (WT) mice (ΔMAP 2 ± 0.8, n = 6). The hPRO-induced pressor response in Syn-hPRR mice is unaffected by co-infusion with the Ang II type 1 receptor blocker losartan (ΔMAP 19 ± 5.2, n = 8), suggesting that the response is independent of Ang II. Interestingly, co-infusion with an inhibitor of the reactive oxygen species-generating enzyme NADPH oxidase (NOX), diphenyleneiodonium, nearly abolishes the hPRO-induced pressor response in Syn-hPRR mice (ΔMAP 4.7 ± 1.0, n = 4), indicating that NOX activity is required. Additionally, we find that basal NOX activity is enhanced in the Syn-hPRR hypothalamus relative to WT mice (1.4 fold change). We next examined which NOX isoform is responsible for the hPRO-induced pressor response and enhanced activity. NOX4 mRNA levels are greater (2.7 ± 0.6 fold change), but NOX1 (1.2 ± 0.3 fold change) and NOX2 (1.2 ± 0.3 fold change) mRNA levels are not different, in the hypothalamus of Syn-hPRR compared to WT mice (n = 3). Adenovirus-mediated delivery of NOX2, NOX4, or a scrambled sequence shRNA was ICV injected in Syn-hPRR mice. After 7 days, we found that treatment with NOX2 (ΔMAP 20 ± 5.2) or scrambled (ΔMAP 23 ± 3.2) shRNA had no effect on the hPRO-induced pressor response (n = 5). However, the hPRO-induced increase in BP is attenuated in Syn-hPRR mice injected with NOX4 shRNA (ΔMAP 5.9 ± 2.8). Together, these data indicate that NOX4 mediates the Ang II-independent pressor response to activation of the human (pro)renin receptor in Syn-hPRR mice.

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BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling

Journal of Neurophysiology ◽

10.1152/jn.00554.2013 ◽

2014 ◽

Vol 111 (5) ◽

pp. 1008-1015 ◽

Cited By ~ 22

Author(s):

Liangfang Zhao ◽

Eric S. Levine

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Metabotropic Glutamate Receptor ◽

Glutamate Release ◽

Brain Slices ◽

Receptor Activation ◽

Inhibitory Synapses ◽

Trkb Receptor ◽

Layer 2

Endogenous cannabinoids (endocannabinoids) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent synaptic modulators that are expressed throughout the forebrain and play critical roles in many behavioral processes. Although the effects of BDNF at excitatory synapses have been well characterized, the mechanisms of action of BDNF at inhibitory synapses are not well understood. Previously we have found that BDNF suppresses presynaptic GABA release in layer 2/3 of the neocortex via postsynaptic tropomyosin-related kinase receptor B (trkB) receptor-induced release of endocannabinoids. To examine the intracellular signaling pathways that underlie this effect, we used pharmacological approaches and whole cell patch-clamp techniques in layer 2/3 pyramidal neurons of somatosensory cortex in brain slices from juvenile Swiss CD1 mice. Our results indicated that phospholipase Cγ (PLCγ) is involved in the CB1 receptor-mediated synaptic effect of BDNF, because the BDNF effect was blocked in the presence of the broad-spectrum PLC inhibitors U-73122 and edelfosine, whereas the inactive analog U-73343 did not alter the suppressive effect of BDNF at inhibitory synapses. Endocannabinoid release can also be triggered by metabotropic glutamate receptor (mGluR)-mediated activation of PLCβ, and BDNF has been shown to enhance spontaneous glutamate release. An mGluR antagonist, E4CPG, however, did not block the BDNF effect. In addition, the effect of BDNF was independent of other signaling pathways downstream of trkB receptor activation, namely, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as protein kinase C signaling.

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Lipid Signaling Pathways in the Heart

Signaling in the Heart ◽

10.1007/978-1-4419-9461-5_7 ◽

2011 ◽

pp. 99-122

Author(s):

José Marín-García

Keyword(s):

Signaling Pathways ◽

Lipid Signaling

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Introduction: Druggable Lipid Signaling Pathways

Druggable Lipid Signaling Pathways - Advances in Experimental Medicine and Biology ◽

10.1007/978-3-030-50621-6_1 ◽

2020 ◽

pp. 1-4

Author(s):

Yasuyuki Kihara

Keyword(s):

Signaling Pathways ◽

Lipid Signaling

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FABP5 coordinates lipid signaling that promotes prostate cancer metastasis

Scientific Reports ◽

10.1038/s41598-019-55418-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Gregory Carbonetti ◽

Tessa Wilpshaar ◽

Jessie Kroonen ◽

Keith Studholme ◽

Cynthia Converso ◽

...

Keyword(s):

Prostate Cancer ◽

Fatty Acid ◽

Lipid Metabolism ◽

Nuclear Receptor ◽

Fatty Acid Synthase ◽

Cancer Metastasis ◽

Receptor Activation ◽

Lipid Signaling ◽

Fatty Acid Binding

AbstractProstate cancer (PCa) is defined by dysregulated lipid signaling and is characterized by upregulation of lipid metabolism-related genes including fatty acid binding protein 5 (FABP5), fatty acid synthase (FASN), and monoacylglycerol lipase (MAGL). FASN and MAGL are enzymes that generate cellular fatty acid pools while FABP5 is an intracellular chaperone that delivers fatty acids to nuclear receptors to enhance PCa metastasis. Since FABP5, FASN, and MAGL have been independently implicated in PCa progression, we hypothesized that FABP5 represents a central mechanism linking cytosolic lipid metabolism to pro-metastatic nuclear receptor signaling. Here, we show that the abilities of FASN and MAGL to promote nuclear receptor activation and PCa metastasis are critically dependent upon co-expression of FABP5 in vitro and in vivo. Our findings position FABP5 as a key driver of lipid-mediated metastasis and suggest that disruption of lipid signaling via FABP5 inhibition may constitute a new avenue to treat metastatic PCa.

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