Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease

Tariq, Kamran; Luikart, Bryan W.

doi:10.37349/ent.2021.00008

Cited by 23 publications

(18 citation statements)

References 230 publications

(233 reference statements)

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“…Another possibility for NM1 regulation of the PI3K pathway could be via competitive binding to phosphatidylinositol (3,4)-bisphosphate (PIP2). PI3K phosphorylates membrane-bound PIP2 to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the balance between PIP2 and PIP3 is critical for cellular homeostasis (Tariq and Luikart, 2021). Dysregulation of lipid signaling could therefore affect the PI3K levels as well.…”

Section: Discussionmentioning

confidence: 99%

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Venit

Sapkota

Abdrabou

et al. 2022

Preprint

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SummaryMetabolic reprogramming is one of the hallmarks of tumorigenesis. Using a combination of multi-omics, here we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. As part of the nutrient-sensing PI3K/Akt/mTOR pathway, NM1 forms a positive feedback loop with mTOR and directly affects mitochondrial oxidative phosphorylation (OXPHOS) via transcriptional regulation of mitochondrial transcription factors TFAM and PGC1α. NM1 depletion leads to suppression of PI3K/Akt/mTOR pathway, underdevelopment of mitochondria inner cristae, and redistribution of mitochondria within the cell, which is associated with reduced expression of OXPHOS genes, decreased mitochondrial DNA copy number and deregulated mitochondrial dynamics. This leads to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis and with a metabolomic profile typical for cancer cells, namely, increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. We show that NM1 KO cells form solid tumors in a nude mouse model even though they have suppressed the PI3K/Akt/mTOR signaling pathway suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient signal for carcinogenesis. We suggest that NM1 plays a key role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the early onset of tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Venit

Sapkota

Abdrabou

et al. 2022

Preprint

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“…Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual specificity protein and lipid phosphatase that counteracts the activity of phosphoinositide 3-kinase (PI3K) by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ) into phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) ( Tariq and Luikart, 2021 ). This negatively regulates the AKT (also known as protein kinase B)/mechanistic target of rapamycin (mTOR) signaling pathway ( Waite and Eng, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss

Tariq¹,

Cullen²,

Getz³

et al. 2022

Cell Reports

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“…First, PLC inhibition, which should also increase the amount of PIP2, paradoxically had the opposite effect in our system: it enhanced endocytosis. The reactivation of PI3K through the turn-off of its PKC inhibition may partially explain it (for a detailed review of PIP2/PIP3 metabolism, see 63 , 64 ). Another controversy is that the inhibition of PTEN, which dephosphorylates PIP3 to PIP2 and acts opposite to PI3K, failed to influence endocytosis (we used two treatment modalities).…”

Section: Discussionmentioning

confidence: 99%

Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis

et al. 2022

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In pneumococcal meningitis, bacterial growth in the cerebrospinal fluid results in lysis, the release of toxic factors, and subsequent neuroinflammation. Exposure of primary murine glia to Streptococcus pneumoniae lysates leads to strong proinflammatory cytokine and chemokine production, blocked by inhibition of the intracellular innate receptor Nod1. Lysates enhance dynamin-dependent endocytosis, and dynamin inhibition reduces neuroinflammation, blocking ligand internalization. Here we identify the cholesterol-dependent cytolysin pneumolysin as a pro-endocytotic factor in lysates, its elimination reduces their proinflammatory effect. Only pore-competent pneumolysin enhances endocytosis in a dynamin-, phosphatidylinositol-3-kinase- and potassium-dependent manner. Endocytic enhancement is limited to toxin-exposed parts of the membrane, the effect is rapid and pneumolysin permanently alters membrane dynamics. In a murine model of pneumococcal meningitis, mice treated with chlorpromazine, a neuroleptic with a complementary endocytosis inhibitory effect show reduced neuroinflammation. Thus, the dynamin-dependent endocytosis emerges as a factor in pneumococcal neuroinflammation, and its enhancement by a cytolysin represents a proinflammatory control mechanism.

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Striking a balance: PIP2 and PIP3 signaling in neuronal health and disease

Cited by 23 publications

References 230 publications

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Regulation of oxidative phosphorylation by Nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice

Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss

Pneumolysin boosts the neuroinflammatory response to Streptococcus pneumoniae through enhanced endocytosis

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