Search results for NCF1

Showing 16 results out of 17

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Protein (4 results from a total of 4)

Identifier: R-HSA-1222296
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P14598
Identifier: R-HSA-1996220
Species: Homo sapiens
Compartment: phagolysosome
Primary external reference: UniProt: NCF1: P14598
Identifier: R-HSA-9626854
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P14598
Identifier: R-HSA-9626824
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P14598

Reaction (7 results from a total of 8)

Identifier: R-HSA-9626817
Species: Homo sapiens
Compartment: cytosol
Neutrophil cytosolic factor 1 (NCF1, also known as p47phox) is a component of the NADPH oxidase (NOX2) complex, which consists of six subunits (Groemping Y et al. 2003; El-Benna J et al. 2005). Two of these subunits, p22phox and gp91phox, are integral membrane proteins and form a heterodimeric flavocytochrome that constitutes the catalytic core of the enzyme. The remaining oxidase components reside in the cytosol and include the small GTPase Rac, as well as a complex of NCF4 (p40phox), NCF1, and NCF2 (p67phox) (Groemping Y et al. 2003; El-Benna J et al. 2005). In the resting state, the interaction of NCF1 (p47phox) with p22phox, and thereby translocation and NADPH oxidase activation, is prevented by an auto-inhibited conformation of NCF1 (Groemping Y et al. 2003; Yuzawa S et al. 2004). This is believed to arise from an intramolecular interaction of the SH3 domains with the C-terminal auto‐inhibitory region (AIR) (amino acids 292‐340) of NCF1 to keep the protein ‘locked’ (Groemping Y et al. 2003; El Benna J et al. 2016). Priming induced by TNF-α or GM-CSF induces NCF1 phosphorylation on Ser345, activation of the proline isomerase PIN1, which binds to NCF1 to induce conformational changes (Boussetta T et al. 2010). This process facilitates extensive phosphorylation of NCF1 by PKC on other sites and induces full opening of NCF1 (Boussetta T et al. 2010). Phosphorylation studies showed that p47phox is phosphorylated on serines located between Ser303 and Ser379 (El Benna J et al. 1994; 2009). Most of these sites correspond to PKC consensus phosphorylation sites, and PKCα, -β, -δ and -ζ were all shown to phosphorylate NCF1 (p47phox) in vitro or in human neutrophil‐like HL‐60 cells (Dang PM et al. 2001; Fontayne A et al. 2002; Belambri SA et al. 2018). In vitro studies also showed that phosphorylation of p47phox induced its binding to the proline rich region (PRR) of p22phox and enhanced the binding of NCF2 (p67phox) to gp91phox (Fontayne A et al. 2002; Dang PMC et al. 2002; Boussetta T et al. 2010).

The Reactome event depicts the PKC-mediated phosphorylation of NCF1 on Ser303, Ser304, Ser320, Ser328, Ser348. However, NCF1 becomes phosphorylated by PKCs on multiple sites and the number of sites is not defined.

Identifier: R-HSA-9626880
Species: Homo sapiens
Compartment: cytosol
In resting cells, the neutrophil cytosolic factor 1 (NCF1, also known as p47phox), NCF2 (p67phox), and NCF4 (p40phox) are located in the cytosol where they associate in a trimer complex with a 1:1:1 stoichiometry through specific domains (Groemping Y & Rittinger K 2005; El-Benna J et al. 2005; Park JW et al. 1994; Lapouge K et al. 2002; El-Benna J et al. 2016). However, NCF1 may also exist separately from the trimer (El-Benna J et al. 2016). In the resting state, two SH3 domains of NCF1 (p47phox) bind the auto‐inhibitory region (AIR; amino acids 292‐340) to keep NCF1 in a closed auto‐inhibited state, preventing its binding to p22phox and therefore NOX2 activation (Groemping Y et al. 2003; Yuzawa S et al. 2004; El-Benna J et al. 2016). Priming of neutrophils by several agents such as GM‐CSF, TNFα, PAF, LPS and CL097, a TLR7/8 agonist, induces partial phosphorylation of NCF1 (Makni-Maalej K et al. 2015; Dang PM et al. 1999; Dewas C et al. 2003; DeLeo FR et al. 1998). Mass spectrometry analysis of NCF1 identified Ser345 as the phosphorylated site in human neutrophils primed by TNFα and GM‐CSF (Dang PMC et al. 2006). Site‐directed mutagenesis of Ser345 and use of a competitive inhibitory peptide containing the Ser345 sequence have demonstrated that this step is critical for the priming of ROS production in human neutrophils (Dang PMC et al. 2006). Further, inhibitors of the p38 MAPK abrogated TNF-alpha- and TLR8 agonist-induced phosphorylation of Ser345 (Dang PMC et al. 2006; Makni-Maalej K et al. 2015).
Identifier: R-HSA-9626832
Species: Homo sapiens
Compartment: cytosol
In resting cells, the NADPH oxidase components, NCF1 (p47phox), NCF2 (p67phox), and NCF4 (p40phox) are located in the cytosol where they associate in a trimer complex with a 1:1:1 stoichiometry through specific domains (Groemping Y & Rittinger K 2005; El-Benna J et al. 2005; Park JW et al. 1994; Lapouge K et al. 2002; El-Benna J et al. 2016). However, NCF1 may also exist separately from the trimer (El-Benna J et al. 2016). In the resting state, two SH3 domains of NCF1 (p47phox) bind the auto‐inhibitory region (AIR; amino acids 292‐340) to keep NCF1 in a closed auto‐inhibited state, preventing its binding to p22phox and therefore NOX2 activation (Groemping Y et al. 2003; Yuzawa S et al. 2004; El-Benna J et al. 2016). Priming of neutrophils by several agents such as GM‐CSF, TNFα, PAF, LPS and CL097, a TLR7/8 agonist, induces partial phosphorylation of NCF1 (Makni-Maalej K et al. 2015; Dang PM et al. 1999; Dewas C et al. 2003; DeLeo FR et al. 1998). Mass spectrometry analysis of NCF1 identified Ser345 as the phosphorylated site in neutrophils primed by TNFα and GM‐CSF, and site‐directed mutagenesis of Ser345 and use of a competitive inhibitory peptide containing the Ser345 sequence have demonstrated that this step is critical for the priming of ROS production in human neutrophils (Dang PMC et al. 2006). Further, inhibitors of the MAPK1 and MAPK3 (ERK1/2) pathway abrogated GM-CSF-induced phosphorylation of Ser345 (Dang PMC et al. 2006).
Identifier: R-HSA-9626816
Species: Homo sapiens
Compartment: cytosol
Priming agents such as tumor necrosis factor-α (TNFα) and toll like receptor 7 (TLR7)/TLR8 agonists induced the activation of the peptidyl-prolyl cis/trans isomerase PIN1 in human neutrophils (Boussetta T et al. 2010; Makni-Maalej K et al. 2015). PIN1 is an enzyme that binds to phosphorylated Ser‐Pro or Thr‐Pro sequences, and subsequently catalyzes their conformational changes (Liou YC et al. 2011). In intact neutrophils, PIN1 was found to bind to the neutrophil cytosol factor 1 (NCF1 or p47phox) via the phosphorylated residue of Ser345 (Boussetta T et al. 2010). PIN1 then catalyzed a conformational change of NCF1 that facilitated subsequent phosphorylation of the protein on other sites by protein kinase C (PKC) (Boussetta T et al. 2010; El-Benna J et al. 2016). Extensive phosphorylation of the subunit NCF1 (p47phox) occurs during the activation of the NADPH oxidase (NOX2) in intact cells.
Identifier: R-HSA-5668731
Species: Homo sapiens
Compartment: cytosol, plasma membrane, extracellular region
While NOX3:CYBA complex has constitutive NADPH oxidase activity, the presence of NCF1, NCF2 or NOXA1 and RAC1:GTP enhances the production of superoxide O2- by the NOX3:CYBA complex. When NCF1 is replaced with NOXO1, RAC1:GTP becomes dispensible for the full activation of the NOX3 complex (Ueno et al. 2005, Ueyama et al. 2006, Miyano and Sumimoto 2007, Kao et al. 2008)
Identifier: R-HSA-5668735
Species: Homo sapiens
Compartment: plasma membrane
Activated RAC1 (RAC1:GTP) binds to the NADPH oxidase NOX3 complex, consisting of NOX3, CYBA (p22phox), NCF1 (p47phox) and NCF2 (p67phox) or NOXA1. RAC1 directly interacts with a conserved region of NOX3 and with tetratricopeptide repeats of NCF2 or NOXA1 (Ueyama et al. 2006, Miyano and Sumimoto 2007, Kao et al. 2008).
Identifier: R-HSA-5668629
Species: Homo sapiens
Compartment: phagolysosome, phagocytic vesicle membrane, cytosol, phagocytic vesicle
RAC2:GTP-bound NOX2 complex, consisting of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40phox), acts as an NADPH oxidase to produce superoxide anion O2- in phagosomes of neutorphils, enabling microbicidal activity of neutrophils (Knaus et al. 1991, Kim et al. 2001, Kao et al. 2008, Anderson et al. 2010, Jyoti et al. 2014). Rac2 knockout mice have dramatically reduced NADPH oxidase activity (Roberts et al. 1999). Phosphorylation of NOX2 complex components NCF1 (el Benna et al. 1994), NCF2 (Zhao et al. 2005) and NCF4 (Bouin et al. 1998) contributes to the activation of the phagosomal NADPH oxidase.

Complex (4 results from a total of 4)

Identifier: R-HSA-9626870
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9626850
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9626814
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9626778
Species: Homo sapiens
Compartment: cytosol

Pathway (1 results from a total of 1)

Identifier: R-HSA-5668599
Species: Homo sapiens
Compartment: cytosol, plasma membrane, phagocytic vesicle membrane, phagolysosome
NADPH oxidases (NOX) are membrane-associated enzymatic complexes that use NADPH as an electon donor to reduce oxygen and produce superoxide (O2-) that serves as a secondary messenger (Brown and Griendling 2009).

NOX2 complex consists of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40ohox). RAC1:GTP binds NOX2 complex in response to VEGF signaling by directly interracting with CYBB and NCF2, leading to enhancement of VEGF-signaling through VEGF receptor VEGFR2, which plays a role in angiogenesis (Ushio-Fukai et al. 2002, Bedard and Krause 2007). RAC2:GTP can also activate the NOX2 complex by binding to CYBB and NCF2, leading to production of superoxide in phagosomes of neutrophils which is necessary fo the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014).

NOX1 complex (composed of NOX1, NOXA1, NOXO1 and CYBA) and NOX3 complex (composed of NOX3, CYBA, NCF1 amd NCF2 or NOXA1) can also be activated by binding to RAC1:GTP to produce superoxide (Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).

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