Phosphatidic acid in neuronal development: A node for membrane and cytoskeleton rearrangements

Ammar, Mohamed-Raafet; Kassas, Nawal; Bader, Marie‐France; Vitale, Nicolas

doi:10.1016/j.biochi.2014.07.026

Cited by 48 publications

(41 citation statements)

References 101 publications

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“…The physical properties of PA influence membrane curvature and allows for PA to act as a signaling lipid by recruiting cytosolic proteins to appropriate membranes [15]. Overexpression of PLD2 leads to an increase in de novo DNA synthesis and has been shown to regulate cell motility and proliferation [16–19].…”

Section: Introductionmentioning

confidence: 99%

A Phosphatidic Acid (PA) conveyor system of continuous intracellular transport from cell membrane to nucleus maintains EGF receptor homeostasis

et al. 2016

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The intracellular concentration of the mitogen phosphatidic acid (PA) must be maintained at low levels until the need arises for cell proliferation. How temporal and spatial trafficking of PA affects its target proteins in the different cellular compartments is not fully understood. We report that in cancer cells, PA cycles back and forth from the cellular membrane to the nucleus, affecting the function of epidermal growth factor (EGF), in a process that involves PPARα/LXRα signaling. Upon binding to its ligand, EGF receptor (EGFR)-initiated activation of phospholipase D (PLD) causes a spike in intracellular PA production that forms vesicles transporting EGFR from early endosomes (EEA1 marker) and prolonged internalization in late endosomes and Golgi (RCAS marker). Cells incubated with fluorescent-labeled PA (NBD-PA) show PA in “diffuse” locations throughout the cytoplasm, punctae (small, <0.1 μm) vesicles) and large (>0.5 μm) vesicles that co-localize with EGFR. We also report that PPARα/LXRα form heterodimers that bind to new Responsive Elements (RE) in the EGFR promoter. Nuclear PA enhances EGFR expression, a role compatible with the mitogenic ability of the phospholipid. Newly made EGFR is packaged into PA recycling vesicles (Rab11 marker) and transported back to the cytoplasm and plasma membrane. However, a PLD+PA combination impedes binding of PPARα/LXRα to the EGFR promoter. Thus, if PA levels inside the nucleus reach a certain threshold (>100 nM) PA outcompetes the nuclear receptors and transcription is inhibited. This new signaling function of PLD-PA targeting EGFR trafficking and biphasically modulating its transcription, could explain cell proliferation initiation and its maintenance in cancer cells.

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Section: Introductionmentioning

confidence: 99%

A Phosphatidic Acid (PA) conveyor system of continuous intracellular transport from cell membrane to nucleus maintains EGF receptor homeostasis

et al. 2016

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“…Although phospho-cofilin is inactive in binding to actin, it does activate phospholipase D1 leading to production of membrane phosphatidic acid (Han et al, 2007). Such effects of phospho-cofilin are usually not investigated although this activity could dramatically alter transmembrane signaling since some upstream regulators of Rho family GTPases, such as DOCK2, need to bind phosphatidic acid before they can be activated by phosphatidylinositol phosphates to serve as guanine nucleotide exchange factors for Rho family GTPases (Nishikima et al, 2009; Ammar et al, 2014) (Figure 2). Several DOCK family proteins are expressed in neurons (Gadea and Blangy, 2014).…”

Section: Cofilin Phosphoregulationmentioning

confidence: 99%

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

Shaw

Bamburg

2017

Pharmacology & Therapeutics

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Cofilin is a ubiquitous protein which cooperates with many other actin-binding proteins in regulating actin dynamics. Cofilin has essential functions in nervous system development including neuritogenesis, neurite elongation, growth cone pathfinding, dendritic spine formation, and the regulation of neurotransmission and spine function, components of synaptic plasticity essential for learning and memory. Cofilin’s phosphoregulation is a downstream target of many transmembrane signaling processes, and its misregulation in neurons has been linked in rodent models to many different neurodegenerative and neurological disorders including Alzheimer disease (AD), aggression due to neonatal isolation, autism, manic/bipolar disorder, and sleep deprivation. Cognitive and behavioral deficits of these rodent models have been largely abrogated by modulation of cofilin activity using viral-mediated, genetic, and/or small molecule or peptide therapeutic approaches. Neuropathic pain in rats from sciatic nerve compression has also been reduced by modulating the cofilin pathway within neurons of the dorsal root ganglia. Neuroinflammation, which occurs following cerebral ischemia/reperfusion, but which also accompanies many other neurodegenerative syndromes, is markedly reduced by peptides targeting specific chemokine receptors, which also modulate cofilin activity. Thus, peptide therapeutics offer potential for cost-effective treatment of a wide variety of neurological disorders. Here we discuss some recent results from rodent models using therapeutic peptides with a surprising ability to cross the rodent blood brain barrier and alter cofilin activity in brain. We also offer suggestions as to how neuronal-specific cofilin regulation might be achieved.

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“…Lipids, for many years considered as simple building blocks of biomembranes, have recently emerged as important regulators together with specific proteins in various membrane trafficking processes . Among those lipids, phosphatidic acid (PA) is now recognized to be crucial for exocytosis and endocytosis but also phagocytosis and autophagy (reviewed in References ). The requirement for PA in calcium‐regulated exocytosis is probably one of the best documented .…”

Section: Introductionmentioning

confidence: 99%

Phosphatidic acid metabolism regulates neuroendocrine secretion but is not under the direct control of lipins

et al. 2020

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Phosphatidic acid (PA) produced by phospholipase D1 has been shown to contribute to secretory vesicle exocytosis in a large number of cell models. Among various hypotheses, PA may contribute to recruit and/or activate at the exocytotic site a set of proteins from the molecular machinery dedicated to secretion, but also directly influence membrane curvature thereby favoring membrane rearrangements required for membrane fusion. The release of informative molecules by regulated exocytosis is a tightly controlled process. It is thus expected that PA produced to trigger membrane fusion should be rapidly metabolized and converted in a lipid that does not present similar characteristics. PA‐phosphatases of the lipin family are possible candidates as they convert PA into diacylglycerol. We show here that lipin 1 and lipin 2 are expressed in neuroendocrine cells where they are cytosolic, but also partially associated with the endoplasmic reticulum. Silencing of lipin 1 or 2 did not affect significantly either basal or evoked secretion from PC12 cells, suggesting that it is unlikely that conversion of PA into a secondary lipid by lipins might represent a regulatory step in exocytosis in neurosecretory cells. However, in agreement with a model in which PA‐metabolism could contribute to prevent entering into exocytosis of additional secretory vesicles, ectopic expression of lipin1B‐GFP in bovine chromaffin cells reduced the number of exocytotic events as revealed by carbon fiber amperometry recording. Furthermore, individual spike parameters reflecting fusion pore dynamics were also modified by lipin1B‐GFP, suggesting that a tight control of PA levels represents an important regulatory step of the number and kinetic of exocytotic events.

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Phosphatidic acid in neuronal development: A node for membrane and cytoskeleton rearrangements

Cited by 48 publications

References 101 publications

A Phosphatidic Acid (PA) conveyor system of continuous intracellular transport from cell membrane to nucleus maintains EGF receptor homeostasis

A Phosphatidic Acid (PA) conveyor system of continuous intracellular transport from cell membrane to nucleus maintains EGF receptor homeostasis

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

Phosphatidic acid metabolism regulates neuroendocrine secretion but is not under the direct control of lipins

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