Syk Is Required for the Activation of Akt Survival Pathway in B Cells Exposed to Oxidative Stress

Ding, Junyi; Takano, Tomoko; Gao, Sanyang; Han, Weihong; Noda, Chiseko; Yanagi, Shigeru; Yamamura, Hirohei

doi:10.1074/jbc.m004813200

Cited by 63 publications

(67 citation statements)

References 32 publications

(34 reference statements)

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“…Hence, it is unclear whether IKK is inhibited directly by curcumin or was inhibited due to the effect of curcumin on an upstream component. It has been shown that IKK is phosphorylated and NF-B is activated in an Syk-and Akt-dependent manner in response to BCR cross-linking, TNF stimulation, and oxidative stress (22,37,38,46,47,55,56). These findings suggest a critical link between the upstream kinases and the NF-B pathway.…”

Section: Discussionmentioning

confidence: 65%

“…Another possibility is suggested by the link between oxidative stress and Syk activation observed in many cell types including B cells. Stimulation of a B cell line with hydrogen peroxide led to an increase in Syk phosphorylation followed by Akt activation and protection of cells against oxidative stress-induced apoptosis (37,55,65). Although our studies suggest that Syk is a direct target of curcumin, it will be interesting to see whether curcumin also affects reactive oxygen species production and thereby modulates Syk activity in an indirect manner.…”

Section: Discussionmentioning

confidence: 92%

“…5B). In B cells, Akt activation has been shown to be dependent on Syk, as Syk-negative B lymphoma cells have a dramatic reduction in Akt phosphorylation (22,37,38). Activated Syk has been shown to activate PI3K either directly or indirectly through adaptor proteins like B cell adaptor protein (BCAP) (39).…”

Section: In Vitro Akt Is Not a Direct Target Of Curcumin And Curcuminmentioning

confidence: 99%

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Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth

Gururajan

Dasu

Shahidain

et al. 2007

The Journal of Immunology

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Curcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-xL, a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 92%

Section: In Vitro Akt Is Not a Direct Target Of Curcumin And Curcuminmentioning

confidence: 99%

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Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth

Gururajan

Dasu

Shahidain

et al. 2007

The Journal of Immunology

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“…Ras was shown to be required for the mitogenic response, but not the survival response . The survival response has been shown to be mediated via the Akt pathway (Ding et al, 2000;Takano et al, 2000). Thus the expression of Gas6 in spinal motor neurons, dorsal root ganglion neurons, and in developing embryos supports a role for Gas6/Axl in nervous system development and repair after spinal cord injury (Li et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

et al. 2003

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Microarray analysis revealed that transcripts for the Axl and Mer receptor tyrosine kinases are expressed at high levels in O4 ϩ -immunopanned oligodendrocytes isolated from second trimester human fetal spinal cord. In humans the sole known ligand for the Axl/Rse/Mer kinases is growth arrest-specific gene 6 (Gas6), which in the CNS is secreted by neurons and endothelial cells. We hypothesized that Gas6 is a survival factor for oligodendrocytes and receptor activation signals downstream to the phosphatidylinositol 3 (PI3)-kinase/Akt pathway to increase cell survival in the absence of cell proliferation. To test this hypothesis, we grew enriched human oligodendrocytes for 6 d on a monolayer of NIH3T3 cells stably expressing Gas6. CNP ϩ oligodendrocytes on Gas6-secreting 3T3 cells had more primary processes and arborizations than those plated solely on 3T3 cells. Also, a twofold increase in CNP ϩ and MBP ϩ oligodendrocytes was observed when they were plated on the Gas6-secreting cells. The effect was abolished in the presence of Axl-Fc but remained unchanged in the presence of the irrelevant receptor fusion molecule TrkA-Fc. A significant decrease in CNP ϩ /TUNEL ϩ oligodendrocytes was observed when recombinant human Gas6 (rhGas6) was administered to oligodendrocytes plated on poly-L-lysine, supporting a role for Gas6 signaling in oligodendrocyte survival during a period of active myelination in human fetal spinal cord development. PI3-kinase inhibitors blocked the anti-apoptotic effect of rhGas6, whereas a MEK/ERK inhibitor had no effect. Thus Gas6 sustains human fetal oligodendrocyte viability by receptor activation and downstream signaling via the PI3-kinase/Akt pathway.

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“…Peroxynitrite-induced activation of the kinase in primary fibroblasts, on the other hand, was found to rely on the PDGF receptor and was not affected by inhibitors of EGF signaling (Klotz et al, 2000). Hydrogen peroxide-induced Akt activation in B cells requires Syk, a non-receptor protein tyrosine kinase (PTK), which is known to play a critical role in B cell receptormediated signaling (Ding et al, 2000). Another non-receptor PTK, focal adhesion kinase, has been implicated in the activation of Akt in glioblastoma cells (Sonoda et al, 1999).…”

Section: Pi3-kinase/akt Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,094

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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Syk Is Required for the Activation of Akt Survival Pathway in B Cells Exposed to Oxidative Stress

Cited by 63 publications

References 32 publications

Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth

Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Cellular response to oxidative stress: Signaling for suicide and survival*

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