Granulocyte-Macrophage Colony-stimulating Factor-activated Signaling Pathways in Human Neutrophils

Al-Shami, Amin; Naccache, Paul H.

doi:10.1074/jbc.274.9.5333

Cited by 81 publications

(31 citation statements)

References 72 publications

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“…Several other reports provided further evidence for coordinated activation of PI3-K and Stat proteins leading to the functional cooperation of both signaling cascades (47,48). Moreover, recent studies demonstrated the ability of Jaks to associate with and to regulate the p85 subunit of PI3-K, as was shown for Jak3 in human T cells (49), Jak1 in cardiac myocytes (50), and Jak2 in human neutrophils (51).…”

Section: Discussionmentioning

confidence: 65%

Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction

Kusch

Tkachuk

Haller³

et al. 2000

Journal of Biological Chemistry

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Janus kinases Jak1 and Tyk2 play an important role in urokinase-type plasminogen activator (uPA)-dependent signaling. We have recently demonstrated that both kinases are associated with the uPA receptor (uPAR) and mediate uPA-induced activation of signal transducers and activators of transcription (Stat1, Stat2, and Stat4) in human vascular smooth muscle cells (VSMC). Janus kinases are not only required for Stat activation but may also interfere with other intracellular signaling pathways. Here we report that in VSMC, Tyk2 interacts with a downstream signaling cascade involving phosphatidylinositol 3-kinase (PI3-K). We demonstrate that uPA induces PI3-K activation, which is abolished in VSMC expressing the dominant negative form of Tyk2. The regulatory subunit p85 of PI3-K co-immunoprecipitates with Tyk2 but not with Jak1, Jak2, or Jak3, and uPA stimulation increases the PI3-K activity in Tyk2 immunoprecipitates. Tyk2 directly binds to either of the two Src homology 2(SH2)p85 domains in a uPA-dependent fashion. We provide evidence that the Tyk2-mediated PI3-K activation in response to uPA is required for VSMC migration. Thus, two unrelated structurally distinct specific inhibitors of PI3-K, wortmannin and LY294002, prevent VSMC migration induced by uPA. No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2. Our results underscore the versatile function of Tyk2 in uPA-related intracellular signaling and indicate that PI3-K plays a selective role in the regulation of VSMC migration.

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Section: Discussionmentioning

confidence: 65%

Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction

Kusch

Tkachuk

Haller³

et al. 2000

Journal of Biological Chemistry

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“…Each member has a conserved C-terminal kinase domain. Jak2 was reported to activate PI-3K␣, but the exact mechanism by which these two molecules interact is unclear (50). This Jak2-dependent PI-3K␣ pathway is unlikely to signal LPC-induced eNOS promoter function, because transfection of ⌬p85, which blocks PI-3K␣ activity, had no effect of eNOS promoter activity.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Endothelial Nitric-oxide Synthase Promoter by the Phosphatidylinositol 3-Kinase γ/Janus Kinase 2/MEK-1-dependent Pathway

Cieslik¹,

Abrams²,

Wu³

2001

Journal of Biological Chemistry

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AG-490, a selective inhibitor of Janus kinase 2 (Jak2), also reduced the LPC-induced Sp1 binding and eNOS promoter activity to the basal level. LPC induced Jak2 phosphorylation, which was abolished by LY 294002 and the dominant negative mutant of PI-3K␥. LY 294002 and AG-490 abrogated MEK-1 phosphorylation induced by LPC but had no effect on Raf-1. These results indicate that PI-3K␥ and Jak2 are essential for LPC-induced eNOS promoter activity. This signaling pathway was sensitive to pertussis toxin, suggesting the involvement of a G i protein in PI-3K␥ activation. These results indicate that LPC enhances Sp1-dependent eNOS promoter activity by a pertussis toxin-sensitive, Ras-independent novel pathway, PI-3K␥/Jak2/MEK-1/ERK1/2.

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“…We have previously demonstrated that GM-CSFinduced neutrophil survival requires Src-kinase-mediated activation of PI3K [26]. Others have found the involvement of JAK2 in GM-CSF-mediated granulocyte survival [27][28][29].…”

Section: Pi3k Signalling and Granulocyte Apoptosismentioning

confidence: 99%

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

Lindemans

Coffer

2004

Biochemical Society Transactions

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Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.

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Granulocyte-Macrophage Colony-stimulating Factor-activated Signaling Pathways in Human Neutrophils

Cited by 81 publications

References 72 publications

Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction

Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction

Up-regulation of Endothelial Nitric-oxide Synthase Promoter by the Phosphatidylinositol 3-Kinase γ/Janus Kinase 2/MEK-1-dependent Pathway

Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase

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