Generation of N-Acylphosphatidylethanolamine by Members of the Phospholipase A/Acyltransferase (PLA/AT) Family

Uyama, Toru; Ikematsu, Natsuki; Inoue, Manami; Shinohara, Naoki; Jin, Xu; Tsuboi, Kazuhito; Tonai, Takeharu; Tokumura, Akira; Ueda, Natsuo

doi:10.1074/jbc.m112.368712

Cited by 66 publications

(75 citation statements)

References 42 publications

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“…Previously, we suggested that the overexpression of PLA/ AT-2 (HRASLS2) also causes the dysfunction of peroxisomes (28), whereas PLA/AT-1 (HRASLS1, A-C1) did not appear to affect peroxisomal functions (45). In the present study, we observed that PLA/AT-2 inhibited the binding of Pex19p to Pex3p and Pex11␤p and decreased the protein level of PMP70.…”

Section: Discussionsupporting

confidence: 63%

“…Thus, we proposed to rename HRASLS1 to 5 as phospholipase/acyltransferase-1 to -5 (PLA/AT-1 to -5), respectively (26). Unexpectedly, we found that the overexpression of PLA/AT-3 (HRASLS3, H-rev107, or AdPLA) or PLA/ AT-2 (HRASLS2) in mammalian cells results in the disappearance of peroxisome membrane structure and the dysfunction of peroxisomes, as revealed by a remarkable decrease in the intracellular levels of ether-type lipids (27,28). The disappearance of peroxisomes was dependent on the enzyme activity of PLA/ AT-3 because the mutant devoid of enzyme activity failed to affect peroxisome functions (27).…”

mentioning

confidence: 94%

“…The deletion mutants (PLA/AT-3-⌬N10-FL and PLA/AT-3-⌬C27-FL) were also constructed using the expression vector harboring mouse PLA/AT-3-FL. C-terminally FLAG-tagged PLA/AT-2 (PLA/AT-2-FL) was constructed using pEF1/Myc-His vector harboring N-terminally FLAG-tagged human PLA/AT-2 (28), and the obtained DNA fragment was subcloned into pEF6/Myc-His. The expression vector pEF6/Myc-His harboring C-terminally FLAG-tagged human PLA/AT-1 (PLA/AT-1-FL) was constructed as reported previously (26).…”

Section: Materials-12-[1-mentioning

confidence: 99%

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Interaction of Phospholipase A/Acyltransferase-3 with Pex19p

Uyama

Kawai

Kono

et al. 2015

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 94%

Section: Materials-12-[1-mentioning

confidence: 99%

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Interaction of Phospholipase A/Acyltransferase-3 with Pex19p

Uyama

Kawai

Kono

et al. 2015

Journal of Biological Chemistry

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“…34,35 In addition, RARRES3 has recently been shown to display phospholipase PLA 1/2 and acyltransferase activities in in vivo and in vitro studies. 36,37 Furthermore, previous studies on the tumorsuppressive effect of RARRES3 focused primarily on the characterization of its functional domains and its physiological targets, while few reports have investigated the implications of its enzymatic activity. Because acylation of signaling proteins is important for the maintenance of cell physiological responses, it is assumed that the enzymatic activity of RARRES3 may be closely linked to its tumorsuppressive effect.…”

mentioning

confidence: 99%

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Hsu

Chan

et al. 2014

Cell Death Differ

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The Wnt/β-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/β-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/β-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelialmesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/β-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/β-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.

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“…[1,[2][3][4][5][6][7][8][9][10][11][12][13][14] C]ethanolamine HCl was from Moravek Biochemicals (Brea, CA). Horseradish peroxidaselinked anti-mouse and anti-rabbit IgGs were from GE Healthcare (Piscataway, NJ).…”

Section: 2-[1′-mentioning

confidence: 99%

Comparative analyses of isoforms of the calcium-independent phosphatidylethanolamine N-acyltransferase PLAAT-1 in humans and mice

Hussain

Uyama

Kawai

et al. 2016

Journal of Lipid Research

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Fatty acyl ethanolamides [N-acylethanolamines (NAEs)] are a class of lipid mediators. Among them, arachidonoylethanolamide (anandamide) is known to be an endogenous ligand of cannabinoid receptors (namely, an endocannabinoid) (1). In addition, palmitoylethanolamide and oleoylethanolamide show biological activities such as antiinflammation, analgesia, and appetite suppression via different receptors including PPAR- (2-5). These NAEs are biosynthesized principally through a two-step pathway from membrane glycerophospholipids via N-acylphosphatidylethanolamines (NAPEs) (6). The first reaction is the transfer of an acyl chain from a glycerophospholipid molecule such as phosphatidylcholine (PC) to the amino group of phosphatidylethanolamine (PE), resulting in the formation of NAPE, and the enzyme responsible is known as PE N-acyltransferase. Very recently, cPLA 2 ɛ, a member of the cytosolic phospholipase A 2 (PLA 2 ) family (PLA2G4), has been identified as the calcium-stimulated N-acyltransferase capable of catalyzing this step (7). However, a series of our recent studies revealed that five members of the HRAS-like suppressor (HRASLS) family, which were originally discovered as tumor suppressors, possess calciumindependent phospholipid-metabolizing activities including NAPE-forming N-acyltransferase and PLA 1/2 activities (8-12), and we proposed to give HRASLS-1-5 the names phospholipase A/acyltransferase-1-5 (PLAAT-1-5), respectively (11). Among the five members, PLAAT-1 particularly received our attention because of its relatively high PE N-acyltransferase activity over PLA 1/2 activity in vitro and predominant expression in testis, skeletal muscle, brain, and heart of humans, mice, and rats, where NAPEs accumulate in response to ischemia and inflammation (11,13).Abstract N-Acylphosphatidylethanolamines (NAPEs) are a class of glycerophospholipids, which are known as precursors for different bioactive N-acylethanolamines. We previously reported that phospholipase A/acyltransferase-1 (PLAAT-1), which was originally found in mammals as a tumor suppressor, catalyzes N-acylation of phosphatidylethanolamines to form NAPEs. However, recent online database suggested the presence of an uncharacterized isoform of PLAAT-1 with an extra sequence at the N terminus. In the present study, we examined the occurrence, intracellular localization, and catalytic properties of this longer isoform, as well as the original shorter isoform from humans and mice. Our results showed that human tissues express the longer isoform but not the short isoform at all. In contrast, mice expressed both isoforms with different tissue distribution. Unlike the cytoplasmic localization of the shorter isoform, the long isoform was found in both cytoplasm and nucleus, inferring that the extra sequence harbors a nuclear localization signal. As assayed with purified proteins, neither isoform required calcium for full activity. Moreover, the overexpression of each isoform remarkably increased cellular NAPE levels. These results conclude that the new long is...

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Generation of N-Acylphosphatidylethanolamine by Members of the Phospholipase A/Acyltransferase (PLA/AT) Family

Cited by 66 publications

References 42 publications

Interaction of Phospholipase A/Acyltransferase-3 with Pex19p

Interaction of Phospholipase A/Acyltransferase-3 with Pex19p

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

Comparative analyses of isoforms of the calcium-independent phosphatidylethanolamine N-acyltransferase PLAAT-1 in humans and mice

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