MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils

Coxon, Patricia Y.; Rane, Madhavi J.; Uriarte, Silvia M.; Powell, David W.; Singh, Saurabh; Butt, Waseem; Chen, Qingdan; McLeish, Kenneth R.

doi:10.1016/s0898-6568(03)00074-3

Cited by 83 publications

(105 citation statements)

References 46 publications

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“…The p38 MAPK pathway participates in a number of neutrophil functions critical to generation and regulation of the inflammatory response, including chemotaxis, adherence, respiratory burst activity, degranulation, and cytoskeletal reorganization (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Understanding the molecular mechanisms by which p38 MAPK participates in these responses is hindered by the limited number of targets of p38 MAPK identified to date in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…A number of neutrophil responses, including chemotaxis, granule exocytosis, respiratory burst activity, and production of chemokines, are dependent on the activation of the p38 MAPK pathway (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). MAPK pathways consist of three-kinase modules formed by the terminal MAPKs, which in turn are activated by dual-specificity serine-threonine/tyrosine kinases termed MAP2Ks, which in turn are activated by serine-threonine kinases termed MAP3Ks (13)(14)(15).…”

mentioning

confidence: 99%

“…A number of p38 MAPK substrates have been identified previously in other cell types, including transcription factors such as activating transcription factor 2, kinases such as p38-regulated and -activated kinase and MAPKactivated protein kinase 2 (MAPKAPK-2), 3 and cell cycle regulators such as cyclin D (17)(18)(19)(20). The only p38 MAPK substrates that have been identified in human neutrophils, however, are MAP-KAPK-2 and p47 phox (1,9,10,21). The goal of the present study was to identify p38 MAPK substrates in human neutrophils using a functional proteomic approach developed in our laboratory that combines in vitro phosphorylation of neutrophil lysate by recombinant kinase, separation of proteins by two-dimensional gel electrophoresis, and phosphoprotein identification by MALDI-TOF mass spectrometry (MALDI-TOF MS) (22,23).…”

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confidence: 99%

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Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

Lominadze

Rane

Merchant

et al. 2005

The Journal of Immunology

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The targets of the p38 MAPK pathway that mediate neutrophil functional responses are largely unknown. To identify p38 MAPK targets, a proteomic approach was applied in which recombinant active p38 MAPK and [32P]ATP were added to lysates from unstimulated human neutrophils. Proteins were separated by two-dimensional gel electrophoresis, and phosphoproteins were visualized by autoradiography and identified by MALDI-TOF. Myeloid-related protein-14 (MRP-14) was identified as a candidate p38 MAPK substrate. MRP-14 phosphorylation by p38 MAPK was confirmed by an in vitro kinase reaction using purified MRP-14/MRP-8 complexes. The site of MRP-14 phosphorylation by p38 MAPK was identified by tandem mass spectrometry and site-directed mutagenesis to be Thr113. MRP-14 phosphorylation by p38 MAPK in intact neutrophils was confirmed by [32P]orthophosphate loading, followed by fMLP stimulation in the presence and absence of a p38 MAPK inhibitor, SB203580. Confocal microscopy of Triton X-100 permeabilized neutrophils showed that a small amount of MRP-14 was associated with cortical F-actin in unstimulated cells. fMLP stimulation resulted in a p38 MAPK-dependent increase in MRP-14 staining at the base of lamellipodia. By immunoblot analysis, MRP-14 was present in plasma membrane/secretory vesicle fractions and gelatinase and specific granules, but not in azurophil granules. The amount of MRP-14 associated with plasma membrane/secretory vesicle and gelatinase granule fractions increased after fMLP stimulation in a p38 MAPK-dependent manner. Direct phosphorylation of the MRP-14/MRP-8 complex by p38 MAPK increased actin binding in vitro by 2-fold. These results indicate that MRP-14 is a potential mediator of p38 MAPK-dependent functional responses in human neutrophils.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

Lominadze

Rane

Merchant

et al. 2005

The Journal of Immunology

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“…Four isoforms of p38-MAPK have been identified (␣, ␤, ␥, and ␦), but only the ␣-and ␤-isoforms are sensitive to SB 203580 (33). SB 203580 blocks chemotaxis, superoxide release, chemokine production, and degranulation in human neutrophils (43)(44)(45) and is highly effective in reducing inflammation in a variety of animal models (33,46). As noted above, nearly identical actions are observed when human neutrophils and animal models are treated with either ATLa or LXA 4 (Refs.…”

Section: Discussionmentioning

confidence: 99%

“…The similar anti-inflammatory effects of SB 203580 and LXA 4 /ATLa on isolated neutrophils and in various animal models are consistent with lipoxins targeting the p38-MAPK pathway/cascade. Recent studies with an inhibitory peptide indicate that MAPKAP-K2 mediates many of the p38-MAPK-dependent responses of neutrophils (45). LXA 4 or its aspirin-triggered analogues also block LTB 4 synthesis in isolated neutrophils and PGE 2 production in inflammatory exudates (47,48).…”

Section: Discussionmentioning

confidence: 99%

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Ohira

Bannenberg

Arita

et al. 2004

The Journal of Immunology

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Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4 methyl ester, an aspirin-triggered lipoxin A4-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10–50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

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Syk‐dependent ERK activation regulates IL‐2 and IL‐10 production by DC stimulated with zymosan

et al. 2007

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Zymosan is a particulate yeast preparation that elicits high levels of IL-2 and IL-10 from dendritic cells (DC) and engages multiple innate receptors, including the Syk-coupled receptor dectin-1 and the MyD88-coupled receptor TLR2. Here, we show that induction of IL-2 and IL-10 by zymosan requires activation of ERK MAP kinase in murine DC. Surprisingly, ERK activation in response to zymosan is completely blocked in Sykdeficient DC and unaffected by MyD88 deficiency. Conversely, ERK activation in response to the TLR2 agonist Pam3Cys is completely MyD88 dependent and unaffected by Syk deficiency. The inability of TLR2 ligands in zymosan to couple to ERK may explain the Syk dependence of the IL-2 and IL-10 response in DC and emphasises the importance of Syk-coupled pattern recognition receptors such as dectin-1 in the detection of yeasts. Furthermore, the lack of receptor compensation observed here suggests that responses induced by complex innate stimuli cannot always be predicted by the signalling pathways downstream of individual receptors.

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MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils

Cited by 83 publications

References 46 publications

Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

Myeloid-Related Protein-14 Is a p38 MAPK Substrate in Human Neutrophils

A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils

Syk‐dependent ERK activation regulates IL‐2 and IL‐10 production by DC stimulated with zymosan

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