Phosphorylation of Raf by ceramide-activated protein kinase

Yao, Bei; Zhang, Yuhua; Delikat, Sylvie; Mathias, Shalini; Basu, Soumalee; Kolesnick, Richard

doi:10.1038/378307a0

Cited by 318 publications

(215 citation statements)

References 28 publications

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“…It is therefore possible that unlike TNF-a, cell death induced by D-e-C 8 -Cer and the other ceramide stereoisomers to arises from toxic effects due to the sustained accumulation of unphysiologically high concentrations of ceramide within cells and the prolonged activation of ceramide targets such as the CAPK and CAPP (shown to be maximally activated by 10 mM ceramide). 40,42 The use of ceramide concentrations exceeding 10 mM (25 ± 100 mM) 10,18,45 may test the cell tolerance to unphysiologically high ceramide concentrations, but may not necessarily clarify the importance of ceramide in the cell death signaling initiated by TNF-a. The ceramide concentration generated by TNF-a is significantly less than the intracellular concentration of ceramide in cells treated with D-e-C 8 -Cer (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Karasavvas

Zakeri

1999

Cell Death Differ

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It is commonly assumed that ceramide is a second messenger that transduces signaling leading to apoptosis. We tested this hypothesis by investigating the role of ceramide in TNF-ainitiated apoptotic signaling using the histiocytic lymphoma cell line U937. We found considerable differences between cell killing by TNF-a and by ceramide. U937 cells treated with TNF-a are committed early and irreversibly to the apoptotic pathway and start to die 90 min after treatment. U937 cells treated with ceramide start to die 12 h after the initial treatment. The cell death signaling initiated by TNF-a is transduced within minutes of exposure to TNF-a and it is irreversible. Exogenous ceramide increases the intracellular level of ceramide rapidly, significantly, and well above the physiological levels, within minutes, but cellular commitment to death does not occur until after the first 6 h of incubation. Furthermore, the endogenous ceramide in U937 cells treated with TNF-a increases well after the commitment to the apoptotic pathway. The differences between ceramide and TNF-a in the kinetics and the commitment to the apoptotic pathway suggest that, (a) ceramide is not a second messenger in the apoptotic signaling of TNF-a, (b) ceramide elevations, in TNF-a treated cells, are a consequence rather than a cause of apoptosis and (c) exogenously added ceramide and TNF-a kill cells via different pathways.

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Section: Discussionmentioning

confidence: 99%

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Karasavvas

Zakeri

1999

Cell Death Differ

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“…In all cases the kinase activity of KSR was dispensable, and the mutation of essential catalytic residues did not affect KSR function. To date no bona fide substrate for KSR has been found, and reports that KSR corresponds to ceramide-activated kinase [119] and phosphorylates Raf-1 [120] are disputed [49,112] and have not been widely accepted. It could well be that KSR is genuinely devoid of catalytic activity, and we are witnessing the transition from a kinase to a dedicated scaffolding protein.…”

Section: Holding It Together : Scaffolds and Adapters Ksr And Cnk (Comentioning

confidence: 99%

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch

2000

Biochemical Journal

1,057

118

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The Ras\Raf\MEK (mitogen-activated protein kinase\ERK kinase)\ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway is one of the primordial signalling systems that Nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as proliferation, differentiation, survival and apoptosis. The basic arrangement includes a G-protein working upstream of a core module consisting of three kinases : a MAPK kinase kinase (MAPKKK) that phosphorylates and activates a MAPK kinase (MAPKK), which in turn activates MAPK ( Figure 1). This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. At present we can distinguish six MAPK modules, which share structurally related components, but seem to mediate specific biological responses. For recent reviews on MAPK pathways, the reader is referred to references [1][2][3]. Here we will focus on the regulation of the ERK (extracellular-signal-regulated kinase) pathway, which features Ras as G-protein, Raf as MAPKKK, MEK (MAPK\ERK kinase) as MAPKK and ERK as MAPK.Despite enjoying a decade in the limelight of scientific interest and revealing a plethora of new insights into the circuitry of signalling pathways in general, this pathway still holds many secrets. These pertain mainly to the regulation of Raf, and to a deeper understanding of how specific biological responses are encoded by spatial and temporal changes in the activity and subcellular distribution of the pathway components, and how these fluctuations are orchestrated at the molecular level. Work from many laboratories has highlighted protein-protein interactions as powerful means of co-ordinating signalling processes, most strikingly exemplified by the assembly of multi-protein signalling complexes on activated receptors, or of transcriptionfactor complexes on gene promoters. However, it is becoming Abbreviations used : Bcr, Breakpoint cluster region ; BXB, isolated Raf-1 kinase domain ; CNK, connector-enhancer of KSR ; CK2, casein kinase 2 ; CRD, cysteine-rich domain ; DEF, docking site for ERK, FxFP ; DLK, dual leucine-zipper-bearing kinase ; ERK, extracellular-signal-regulated kinase ; Hsp, heat-shock protein ; KIM, kinase interaction motif ; IκB, inhibitor of NF-κB ; JNK, c-Jun N-terminal kinase ; KSR, kinase suppressor of Ras ; MAPK, mitogen-activated protein kinase ; MAPKK, MAPK kinase ; MAPKKK, MAPK kinase kinase ; MEK, MAPK/ERK kinase ; MEKK, MEK kinase ; MP1, MEK partner 1 ; MUK, MAPK upstream kin...

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“…3 In particular, ceramide activates ceramide-activated protein (CAP) kinase that in turn phosphorylates Raf-1 on Thr 269, increasing its activity towards MEK (MAP kinase or ERK kinase). 4 Moreover, C2 ceramide selectively modulates calpain I expression levels, thus decreasing tau levels in differentiated PC12 cells. 5 The final outcome of C2 ceramide treatment changes according to its concentration and the cellular context.…”

Section: Introductionmentioning

confidence: 99%

Ceramide triggers an NF-κB-dependent survival pathway through calpain

et al. 2005

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We have shown that C2 ceramide, a cell-permeable analog of this lipid second messenger, triggers an NF-jB dependent survival pathway that counteracts cell death. Activation of NF-jB and subsequent induction of prosurvival genes relies on calpain activity and is prevented on silencing of the calpain small subunit (Capn4) that is required for the function of ubiquitous calpains. We have demonstrated that p105 (NFjB1) and its proteolytic product p50 can be targets of microand milli-calpain in vitro and that a p50 deletion mutant, lacking both the N-and the C-terminal ends, is resistant to calpain-mediated degradation. Capn4 silencing results in stabilization of endogenous p105 and p50 in diverse human cell lines. Furthermore, p105 processing and activation of NFjB survival genes in response to C2 ceramide is impaired in Capn4À/À mouse embryonic fibroblasts defective in calpain activity. Altogether, these data argue for the existence of a ceramide-calpain-NF-jB axis with prosurvival functions.

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Phosphorylation of Raf by ceramide-activated protein kinase

Cited by 318 publications

References 28 publications

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Ceramide triggers an NF-κB-dependent survival pathway through calpain

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