An Overview of Class II Phosphoinositide 3-Kinases

Heng, Emily Yan Zhi; Maffucci, Tania

doi:10.1007/978-3-031-06566-8_2

Cited by 3 publications

(2 citation statements)

References 99 publications

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“…Here, we find that PI(3)P levels increase upon cLTP induction, and blocking this increase by inhibition of VPS34 decreases the cLTP-dependent recruitment of SNX17 to endosomal compartments. In the presence of VPS34-INH, there was a partial increase in PI(3)P levels 30 min after the cLTP stimulus, which may be due to the presence of additional sources of PI(3)P. Note that while VPS34 is responsible for a major portion of the PI(3)P pool (Devereaux et al, 2013; Ikonomov et al, 2015), class II phosphatidylinositol 3-kinases and INPP4 phosphatases also contribute to PI(3)P levels (Heng and Maffucci, 2022; Gozzelino et al, 2020; Burke et al, 2022). The sources of PI(3)P at synapses are currently unknown, but our finding that PI(3)P levels increase 30 min after cLTP even in the presence of VPS34-INH suggests that additional sources of PI(3)P are induced by cLTP.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

Rivero-Ríos

Tsukahara

Uygun

et al. 2023

Preprint

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Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway, or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating surface expression of β1-integrin. SNX17 recruitment relies on NMDAR activation, CamKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses, and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.

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Section: Discussionmentioning

confidence: 99%

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

Rivero-Ríos

Tsukahara

Uygun

et al. 2023

Preprint

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“…Thus, the gene expression pattern may shed light on the consistent reduction in endothelial wound healing capacity following ImP treatment. Moreover, we found reduced expression of PIK3C2A, which encodes phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 (Figure 5C), an enzyme that belongs to the phosphoinositide 3-kinase (PI3K) family 32 known to be activated upon insulin receptor stimulation. 33 Western blot analysis confirmed reduced expression of PI3 Kinase Class II α (PI3K(C2A)) also on protein level (Figure 5D).…”

Section: Imidazole Propionate Suppresses Pi3k/akt Signalingmentioning

confidence: 99%

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

Nageswaran,

Carreras,

Reinshagen

et al. 2024

Preprint

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BackgroundThe microbially generated amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effect of ImP on endothelial cell physiology and its role in atherosclerotic coronary artery disease (CAD) is unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis.MethodsPlasma levels of ImP were measured in patients undergoing elective cardiac angiography (n = 831) by means of ultra high-performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios (ORs) and corresponding 95% confidence intervals for CAD were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. Atheroprone apolipoprotein E-/-(Apoe-/-) mice fed a high-fat diet were additionally treated with ImP (800 µg) or vehicle and aortic atherosclerotic lesion area was evaluated after 12 weeks. In a mouse model of carotid artery injury, the effect of ImP on vascular regeneration was examined. Using human aortic endothelial cells (HAECs) the effect of ImP on functional properties of endothelial cells were assessed. Next-generation sequencing, western blot analysis, siRNA-based gene knockdown and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms.ResultsPlasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk for prevalent CAD. In atheroproneApoe-/-mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells, and promoted an increased inflammatory response. Long-term exposure to ImP impaired the repair potential of the endothelium after an arterial insult. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway leading to the sustained activation of the forkhead box protein O1 (FOXO1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of endothelial cells after carotid injury.ConclusionsOur findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.

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Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

Rivero-Ríos

Tsukahara

Uygun

et al. 2023

Journal of Cell Biology

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Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating the surface expression of β1-integrin. SNX17 recruitment relies on NMDAR activation, CaMKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.

show abstract

An Overview of Class II Phosphoinositide 3-Kinases

Cited by 3 publications

References 99 publications

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity

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