Antagonists of Phosphatidylinositol 3-Kinase Block Activation of Several Novel Protein Kinases in Neutrophils

Ding, Jiabing; Vlahos, Chris J.; Liu, Ruichun; Brown, Raymond F.; Badwey, John A.

doi:10.1074/jbc.270.19.11684

Cited by 132 publications

(154 citation statements)

References 44 publications

Supporting

Mentioning

138

Contrasting

Order By: Relevance

“…In addition, inhibition of PI-3K by wortmannin attenuates chemoattractantstimulated ERK and p38 MAPK activity in human PMNs [36][37][38]56]. Because higher concentrations of wortmannin have been reported to inhibit enzymes other than PI-3K [57,58], we examined the effect of 100 nM wortmannin on TNF-␣ and GM-CSF stimulation of ERK and p38 MAPK activity. The ability of wortmannin to inhibit activation of ERKs and p38 MAPK by GM-CSF, but not TNF-␣, suggests that TNF-␣ and GM-CSF receptors activate these MAPK cascades by different signal transduction pathways.…”

Section: Discussionmentioning

confidence: 99%

Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-α and GM-CSF

McLeish

Knall²,

Ward³

et al. 1998

Journal of Leukocyte Biology

152

141

View full text Add to dashboard Cite

The signal transduction pathways activated by tumor necrosis factor ␣ (TNF-␣) and granulocyte-macrophage colony-stimulating factor (GM-CSF) that lead to priming of polymorphonuclear leukocytes (PMNs) are unknown. The hypotheses that these cytokines stimulate multiple mitogen-activated protein kinase (MAPK) cascades, including extracellular signal-regulated kinases (ERKs), c-Jun amino-terminal kinases (JNKs), and p38 MAPK, and that these MAPKs participate in priming of human PMNs were examined. TNF-␣ stimulated a dose-dependent increase in ERK and p38 MAPK activities that was maximal at 10 min. JNKs were not stimulated by TNF-␣ or GM-CSF. GM-CSF stimulated ERK activity comparable to that of TNF-␣, but GM-CSF was a less potent stimulus of p38 MAPK activity. The tyrosine kinase inhibitor, genistein, inhibited ERK and p38 MAPK stimulation by both cytokines. The phosphatidylinositol 3-kinase inhibitor, wortmannin, attenuated stimulation of ERKs and p38 MAPK by GM-CSF, but not TNF-␣. GM-CSF, but not TNF-␣, stimulated wortmannin-sensitive activation of Raf-1. TNF-␣ and GM-CSF priming of superoxide release stimulated by N-formyl-methionyl-leucyl-phenylalanine was significantly attenuated by the MEK inhibitor, PD098059, and the p38 MAPK inhibitor, SB203580. Incubation with both MAPK inhibitors produced an additive effect. Our data suggest that TNF-␣ and GM-CSF activate ERKs and p38 MAPK by different signal transduction pathways. Both ERK and p38 MAPK cascades contribute to the ability of TNF-␣ and GM-CSF to prime the respiratory burst response in human PMNs. J. Leukoc. Biol. 64: 537-545; 1998.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-α and GM-CSF

McLeish

Knall²,

Ward³

et al. 1998

Journal of Leukocyte Biology

152

141

View full text Add to dashboard Cite

show abstract

“…Interestingly, CIS binds stably to the tyrosine phosphorylated ␤c chain [167]. CIS is thought to be a negative reg-LY294002 [154][155][156]. Recently, priming and activation of the PI3K pathway by GM-CSF were shown to take part in ulator of IL-3/IL-5/GM-CSF signalling, because over-expression of CIS represses IL-3-dependent growth [167], oncostatin the activation of the respiratory burst and chemokinesis by GM-CSF in neutrophils [89] and eosinophils [90].…”

Section: Il-3/il-5/gm-csf Receptor Signallingmentioning

confidence: 99%

“…Interestingly, wortmannin blocks FMLP-induced p47phox phosrow-derived macrophages from STAT5A-deficient mice, CIS induction by GM-CSF was markedly inhibited [56]. Inphorylation [156]. Moreover, over-expression of active PI3K in the monoblastic phagocyte cell line GM-1 caused deed, the cis promoter contains four STAT binding sites that are activated by STAT5 [168].…”

Section: Il-3/il-5/gm-csf Receptor Signallingmentioning

confidence: 99%

Regulation of Proliferation, Differentiation and Survival by the IL-3/IL-5/GM-CSF Receptor Family

Groot

Coffer

Koenderman

1998

Cellular Signalling

191

153

View full text Add to dashboard Cite

ABSTRACT. The receptors for the Il-3/IL-5/GM-CSF cytokine family are composed of a heterodimeric complex of a cytokine-specific ␣ chain and a common ␤ chain (␤c). Binding of IL-3/IL-5/GM-CSF to their respective receptors rapidly induces activation of multiple intracellular signalling pathways, including the Ras-Raf-ERK, the JAK/STAT, the phosphatidylinositol 3-kinase PKB, and the JNK/SAPK and p38 signalling pathways. This review focuses on recent advancements in understanding how these different signalling pathways are activated by IL-3/IL-5/GM-CSF receptors, and how the individual pathways contribute to the pleiotropic effects of IL-3/IL-5/GM-CSF on their target cells, including proliferation, differentiation, survival, and effector functions. cell signal 10;9:619-628, 1998.

show abstract

“…Paks are Ser/Thr protein kinases that undergo autophosphorylation/activation upon interacting with the active (GTP-bound) forms of the small GTPases(p21) Rac or Cdc42 (11). Activation of the Paks in neutrophils can be blocked by inhibitors of heterotrimeric G proteins (pertussis toxin) (2,5), phosphatidylinositol 3-kinase (PI 3-K; i.e., wortmannin, LY 294002) (12), and tyrosine kinases (13,14). Paks or Pak-like kinases contain binding sites for the ␤␥-subunits of complex G proteins (15), guanine nucleotide exchange factors (GEF; i.e., Pakinteracting exchange factors) (16), and adaptor proteins (Nck) (17,18).…”

mentioning

confidence: 99%

Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Lian

Crossley

Zhan

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Neutrophils stimulated with fMLP or a variety of other chemoattractants that bind to serpentine receptors coupled to heterotrimeric G proteins exhibit rapid activation of two p21-activated protein kinases (Paks) with molecular masses of ∼63 and 69 kDa (γ- and α-Pak). Previous studies have shown that products of phosphatidylinositol 3-kinase and tyrosine kinases are required for the activation of Paks. We now report that a variety of structurally distinct compounds which interrupt different stages in calcium/calmodulin (CaM) signaling block activation of the 63- and 69-kDa Paks in fMLP-stimulated neutrophils. These antagonists included selective inhibitors of phospholipase C (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione), the intracellular Ca2+ channel (8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate), CaM (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), and CaM-activated protein kinases (N-[2-(N-(chlorocinnamyl)-N-methylaminomethyl)phenyl]-N-[2-hydroxyethyl]-4-methoxybenzenesulfonamide). This inhibition was dose-dependent with IC50 values very similar to those that interrupt CaM-dependent reactions in vitro. In contrast, less active analogues of these compounds (1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2,5-pyrrolidinedione; N-(6-aminohexyl)-1-naphthalenesulfonamide; N-(4-aminobutyl)-1-naphthalenesulfonamide; promethazine; 2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzyl-amine]) did not affect activation of Paks in these cells. CaM antagonists (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide; trifluoperazine), but not their less-active analogues (N-(6-aminohexyl)-1-naphthalenesulfonamide; promethazine), were also found to block activation of the small GTPases Ras and Rac in stimulated neutrophils along with the extracellular signal-regulated kinases. These data strongly suggest that the Ca2+/CaM complex plays a major role in the activation of a number of enzyme systems in neutrophils that are regulated by small GTPases.

show abstract

Antagonists of Phosphatidylinositol 3-Kinase Block Activation of Several Novel Protein Kinases in Neutrophils

Cited by 132 publications

References 44 publications

Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-α and GM-CSF

Activation of mitogen-activated protein kinase cascades during priming of human neutrophils by TNF-α and GM-CSF

Regulation of Proliferation, Differentiation and Survival by the IL-3/IL-5/GM-CSF Receptor Family

Antagonists of Calcium Fluxes and Calmodulin Block Activation of the p21-Activated Protein Kinases in Neutrophils

Contact Info

Product

Resources

About