Determination of EGFR Endocytosis Kinetic by Auto-Regulatory Association of PLD1 with μ2

Lee, Jun Sung; Kim, Il Shin; Kim, Junghwan; Cho, Wonhwa; Suh, Pann Ghill; Ryu, Sung Ho

doi:10.1371/journal.pone.0007090

Cited by 9 publications

(11 citation statements)

References 25 publications

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“…PLD2 interacts with many different proteins and has been proposed in some contexts to have noncatalytic roles . To address whether PLD activity is key for Agg‐Ox‐LDL phagocytosis, we investigated the ability of small molecule PLD inhibitors to reduce Agg‐Ox‐LDL uptake from macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…PLD2 interacts with many different proteins and has been proposed in some contexts to have noncatalytic roles. 68 To address whether PLD activity is key for Agg-Ox-LDL phagocytosis, we investigated the ability of small molecule PLD inhibitors to reduce Agg-Ox-LDL uptake from macrophages. WT macrophages were cultured in media containing inhibitors that block activity of both PLD1 and PLD2 (FIPI), 60 and relatively selective for PLD1 (VU0155069), 26,69 or selective for PLD2 (VU0364739).…”

Section: Pld Inhibitors Reduce Agg-ox-ldl Phagocytosismentioning

confidence: 99%

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Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2–CD36 functional interdependence

Ganesan

Henkels

Wrenshall

et al. 2018

Journal of Leukocyte Biology

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The uptake of cholesterol carried by low-density lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into "foam cells," an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow-derived macrophages from genetically PLD deficient mice, we demonstrate that PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg-Ox-LDL), which was phenocopied with a PLD2-selective inhibitor. We also report a role for PLD2 in coupling Agg-oxLDL phagocytosis with WASP, Grb2, and Actin. Further, the clearance of LDL particles is mediated by both CD36 and PLD2, via mutual dependence on each other. In the absence of PLD2, CD36 does not engage in Agg-Ox-LDL removal and when CD36 is blocked, PLD2 cannot form protein-protein heterocomplexes with WASP or Actin. These results translated into humans using a GEO database of microarray expression data from atheroma plaques versus normal adjacent carotid tissue and observed higher values for NFkB, PLD2 (but not PLD1), WASP, and Grb2 in the atheroma plaques. Human atherectomy specimens confirmed high presence of PLD2 (mRNA and protein) as well as phospho-WASP in diseased arteries. Thus, PLD2 interacts in macrophages with Actin, Grb2, and WASP during phagocytosis of Agg-Ox-LDL in the presence of CD36 during their transformation into "foam cells." Thus, this study provides new molecular targets to counteract vascular plaque formation and atherogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Pld Inhibitors Reduce Agg-ox-ldl Phagocytosismentioning

confidence: 99%

Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2–CD36 functional interdependence

Ganesan

Henkels

Wrenshall

et al. 2018

Journal of Leukocyte Biology

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“…In presence of EGF, activated EGFR is internalized via CME with the help of the adaptor protein AP2 that recognizes EGFR via its μ2 subunit. In this context, it was seen that the PLD1 protein itself is an effector of PA and the auto-regulatory interaction between the PX domain of PLD1 and PA promotes the binding of PH domain of PLD1 with μ2 subunit and thereby facilitates EGFR endocytosis (Lee J.S. et al, 2009).…”

Section: Phosphatidic Acid Functionsmentioning

confidence: 99%

Regulation of Membrane Turnover by Phosphatidic Acid: Cellular Functions and Disease Implications

Thakur

Naik

Panda

et al. 2019

Front. Cell Dev. Biol.

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Phosphatidic acid (PA) is a simple glycerophospholipid with a well-established role as an intermediate in phospholipid biosynthesis. In addition to its role in lipid biosynthesis, PA has been proposed to act as a signaling molecule that modulates several aspects of cell biology including membrane transport. PA can be generated in eukaryotic cells by several enzymes whose activity is regulated in the context of signal transduction and enzymes that can metabolize PA thus terminating its signaling activity have also been described. Further, several studies have identified PA binding proteins and changes in their activity are proposed to be mediators of the signaling activity of this lipid. Together these enzymes and proteins constitute a PA signaling toolkit that mediates the signaling functions of PA in cells. Recently, a number of novel genetic models for the analysis of PA function in vivo and analytical methods to quantify PA levels in cells have been developed and promise to enhance our understanding of PA functions. Studies of several elements of the PA signaling toolkit in a single cell type have been performed and are presented to provide a perspective on our understanding of the biochemical and functional organization of pools of PA in a eukaryotic cell. Finally, we also provide a perspective on the potential role of PA in human disease, synthesizing studies from model organisms, human disease genetics and analysis using recently developed PLD inhibitors.

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“…Further, triptolide-induced suppression of PLD expression inhibits proliferation of MDA-MB-231 breast cancer cells [128]. A role for PLD2 phosphorylation has been proposed for the proliferation-inducing capabilities of PLD2 [129, 130]. …”

Section: Functions Of Pldmentioning

confidence: 99%

The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (And a surprise discovery: PLD2 is a GEF)

Gómez‐Cambronero

2011

Cellular Signalling

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PLD catalyzes the conversion of the membrane phospholipid phosphatidylcholine to choline and phosphatidic acid (PA). PLD's mission in the cell is two-fold: phospholipid turnover with maintenance of the structural integrity of cellular/intracellular membranes and cell signaling through PA and its metabolites. Precisely, through its product of the reaction, PA, PLD has been implicated in a variety of physiological cellular functions, such as intracellular protein trafficking, cytoskeletal dynamics, chemotaxis of leukocytes and cell proliferation. The catalytic (HKD) and regulatory (PH and PX) domains were studied in detail in the PLD1 isoform, but PLD2 was traditionally studied in lesser detail and much less was known about its regulation. Our laboratory has been focusing on the study of PLD2 regulation in mammalian cells. Over the past few years, we have reported, in regards to the catalytic action of PLD, that PA is a chemoattractant agent that binds to and signals inside the cell through the ribosomal S6 kinases (S6K). Regarding the regulatory domains of PLD2, we have reported the discovery of the PLD2 interaction with Grb2 via Y169 in the PX domain, and further association to Sos, which results in an increase of de novo DNA synthesis and an interaction (also with Grb2) via the adjacent residue Y179, leading to the regulation of cell ruffling, chemotaxis and phagocytosis of leukocytes. We also review the complex regulation by tyrosine phosphorylation by epidermal growth factor receptor (EGF-R), Janus Kinase 3 (JAK3) and Src and the role of phosphatases. Recently, there is evidence supporting a new level of regulation of PLD2 at the PH domain, by the discovery of CRIB domains and a Rac2-PLD2 interaction that leads to a dual (positive and negative) effect on its enzymatic activity. Lastly, we review the surprising finding of PLD2 acting as a GEF. A phospholipase such as PLD that exists already in the cell membrane that acts directly on Rac allows a quick response of the cell without intermediary signaling molecules. This provides only the latest level of PLD2 regulation in a field that promises newer and exciting advances in the next few years.

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Determination of EGFR Endocytosis Kinetic by Auto-Regulatory Association of PLD1 with μ2

Cited by 9 publications

References 25 publications

Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2–CD36 functional interdependence

Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2–CD36 functional interdependence

Regulation of Membrane Turnover by Phosphatidic Acid: Cellular Functions and Disease Implications

The exquisite regulation of PLD2 by a wealth of interacting proteins: S6K, Grb2, Sos, WASp and Rac2 (And a surprise discovery: PLD2 is a GEF)

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