Cell-free activation of neutrophil NADPH oxidase by a phosphatidic acid-regulated protein kinase.

McPhail, Linda C.; Qualliotine-Mann, Diane; Waite, Kristin

doi:10.1073/pnas.92.17.7931

Cited by 89 publications

(79 citation statements)

References 53 publications

(27 reference statements)

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“…In humans, the scaffold is provided by the sum of NADPH oxidase subunits that bind both a GTPase, Racl, and Pak, a human homologue of Ste20p (Diekmann et al, 1994;Manser et al, 1994;Prigmore et al, 1995). PX domain-containing PtdIns 3-kinases and PLD isoforms may further regulate the mammalian pathway via the activation of protein kinases that phosphorylate p47pho" (Ding et al, 1995;McPhail et al, 1995).…”

Section: Rfisynp-l Ncfi-humnn4 C E Y B L N G B T M a R~e E Y R Kmentioning

confidence: 99%

Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3‐kinases: Binding partners of SH3 domains?

1996

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Two SH3 domain-containing cytosolic components of the NADPH oxidase, p47ph0" and p40phox, are shown by analyses of their sequences to contain single copies of a novel class of domain, the PX (phox) domain. Homologous domains are demonstrated to be present in the Cpk class of phosphatidylinositol 3-kinase, S. cerevisiae Bemlp, and S. pombe Scd2, and a large family of human sorting nexin 1 (SNXI) homologues. The majority of these domains contains a polyproline motif, typical of SH3 domain-binding proteins. Two further findings are reported. A third NADPH oxidase subunit, p67pho", is shown to contain four tetratricopeptide repeats (TPRs) within its N-terminal RacIGTPbinding region, and a 28 residue motif in p40phox is demonstrated to be present in protein kinase C isoforms ~l h and 5; and in three ZZ domain-containing proteins.Keywords: homology; signal transduction; chronic granulomatous disease; tetratrico peptide repeats; phospholipase D Patients with chronic granulomatous diseases (CCDs) are severely predisposed to infection by fungi and bacteria due to deficiencies of the component subunits of NADPH oxidase. Dysfunction of the oxidase reduces superoxide generation, thereby compromising a major non-specific host defense mechanism of phagocytes (reviewed in Segal, 1989). The most common cause of CCDs is an X-linked inheritance, resulting in the deficiency of the large /3 subunit of flavocytochrome b (gp91Ph0"). In approximately 3 U O % of cases, however, autosomally inherited deficiencies of other subunits with masses 47k and 67k (p47phox, and p67pho") lead to CCD (Clark et al., 1989;Let0 et al., 1990). Stimulation of neutrophils or other phagocytes results in these two cytosolic proteins, along with the small GTPases Racl or Rac2, translocating to the plasma membrane; subsequently, they form the functional NADPH oxidase, in complex with the transmembrane and heterodimeric gp9 Iphox-p22phox flavocytochrome b5S8. This is the minimum complex required to generate the microbicidal superoxide anion. An additional cytosolic factor, p40pho", is known also to associate with the NADPH oxidase complex (Wientjes et al., 1993), although its regulatory roles remain uncertain.P40PhoX, p47phox, and p67phoX each contain Src homology 3 (SH3) domains, which mediate multiple associations with proline-rich targets within the NADPH oxidase complex (Fuchs et al., 1995;de Mendez et al., 1996). These domains are also present in a diverse range of kinases, phosphatases, phospholipases, and cytoskeletal proteins, and bind left-handed polyproline type I1 helices (reviewed in Pawson, 1995). The presence of other domain types in p47ph0" and p67phox, however, has not previously been noted. Here I report the identification of a novel domain family that includes p40phox, p47phox, phosphatidylinositol (PtdIns) 3-kinases, homologues of a sorting nexin (SNXI), and several yeast proteins, including the SH3-containing protein, Bemlp. 1 also record the presence of tetratricopeptide repeats (TPRs) in p67pho", and note that a 28 residue (oct...

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Section: Rfisynp-l Ncfi-humnn4 C E Y B L N G B T M a R~e E Y R Kmentioning

confidence: 99%

Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3‐kinases: Binding partners of SH3 domains?

1996

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“…PA also appears to have inhibitory effects on Ras-GTPase-activating proteins (252) and Rho-GTP-dissociating isoforms (37; reviewed in Refs. 19,115,126,155).…”

Section: As Indicated In Substrates Formentioning

confidence: 99%

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Nanjundan

Possmayer

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg2+ dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg2+independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.

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“…PA has been shown to partially activate purified flavocytochrome b 558 (23), suggesting it interacts with this protein. It is not known whether DG has any direct effect(s) on NADPH oxidase components.Previous studies examined NADPH oxidase activation by PA plus DG in a cell-free system consisting of membrane and cytosolic fractions from human neutrophils (16,17,24). Both lipids are required for optimal activation (16, 17), but the individual roles of each are not clear.…”

mentioning

confidence: 99%

“…Previous studies examined NADPH oxidase activation by PA plus DG in a cell-free system consisting of membrane and cytosolic fractions from human neutrophils (16,17,24). Both lipids are required for optimal activation (16,17), but the individual roles of each are not clear.…”

mentioning

confidence: 99%

Phosphatidic Acid and Diacylglycerol Directly Activate NADPH Oxidase by Interacting with Enzyme Components

Palicz

Foubert

Jesaitis

et al. 2001

Journal of Biological Chemistry

112

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The enzyme NADPH oxidase is regulated by phospholipase D in intact neutrophils and is activated by phosphatidic acid (PA) plus diacylglycerol (DG) in cell-free systems. We showed previously that cell-free NADPH oxidase activation by these lipids involves both protein kinase-dependent and -independent pathways. Here we demonstrate that only the protein kinase-independent pathway is operative in a cell-free system of purified and recombinant NADPH oxidase components. Activation by PA ؉ DG was ATP-independent and unaffected by the protein kinase inhibitor staurosporine, indicating the lack of protein kinase involvement. Both PA and DG were required for optimal activation to occur. The drug R59949 reduced activation of NADPH oxidase by either arachidonic acid or PA ؉ DG, with IC 50 values of 46 and 25 M, respectively. The optimal concentration of arachidonic acid or PA ؉ DG for oxidase activation was shifted to the right with R59949, indicating interference of the drug with the interaction of lipid activators and enzyme components. R59949 inhibited the lipid-induced aggregation/sedimentation of oxidase components p47 phox and p67 phox , suggesting a disruption of the lipidmediated assembly process. The direct effects of R59949 on NADPH oxidase activation complicate its use as a "specific" inhibitor of DG kinase. We conclude that the protein kinase-independent pathway of NADPH oxidase activation by PA and DG involves direct interaction with NADPH oxidase components. Thus, NADPH oxidase proteins are functional targets for these lipid messengers in the neutrophil.The NADPH oxidase (the respiratory burst enzyme) in phagocytic cells produces superoxide (O 2 . ) 1 by catalyzing electron transfer from NADPH to molecular oxygen upon cell stimulation (1-3). This enzyme plays important roles in host defense against infection and in tissue damage due to inflammation (1-5). In addition, NADPH oxidase-like enzymes are present in a variety of other cell types, where the oxygen radicals formed may have signaling roles (5, 6). The enzyme in phagocytes consists of the membrane-bound heterodimeric flavocytochrome b 558 (gp91 phox and p22 phox ) and four cytosolic proteins (p47 phox , p67 phox , p40 phox , Rac1/2) (2-4, 7). Components must assemble in the membrane for the enzyme to become active (2-4, 7). The activation of NADPH oxidase is initiated by receptor-ligand interaction and involves complex intracellular signaling events. These include the activation of protein kinases to phosphorylate cellular proteins and NADPH oxidase components (2, 8) and the generation of various lipid second messengers (AA by phospholipase A 2 (9); DG by phospholipase C or PA phosphohydrolase; PA by phospholipase D or DG kinase (10, 11)). In cell-free systems, these lipids can induce activation of the enzyme (12-17). AA exerts its effect by directly acting on enzyme components (18 -22). PA has been shown to partially activate purified flavocytochrome b 558 (23), suggesting it interacts with this protein. It is not known whether DG has any direct effe...

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Cell-free activation of neutrophil NADPH oxidase by a phosphatidic acid-regulated protein kinase.

Cited by 89 publications

References 53 publications

Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3‐kinases: Binding partners of SH3 domains?

Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3‐kinases: Binding partners of SH3 domains?

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase

Phosphatidic Acid and Diacylglycerol Directly Activate NADPH Oxidase by Interacting with Enzyme Components

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