Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling

Ga, Müller; Störz, Peter; Bourteele, Soizic; Döppler, Heike; Pfizenmaier, Klaus; Mischak, Harald; Philipp, Alex; Kaiser, Christian; Kölch, Walter

doi:10.1093/emboj/17.3.732

Cited by 104 publications

(79 citation statements)

References 64 publications

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“…If the CRD binds too strongly, activation does not occur. These findings could explain the paradoxical observation that ceramide enhances Raf-1 binding to Ras, but produces a complex unresponsive to activation [49]. In addition, these findings help to explain the paradoxical observation that in some cell types, such as PC12, cAMP can facilitate ERK activation despite inhibiting Raf-1 [50].…”

Section: Figure 4 Multi-protein Signalling Complexesmentioning

confidence: 83%

“…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%

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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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Section: Figure 4 Multi-protein Signalling Complexesmentioning

confidence: 83%

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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“…Thus, it is possible that TNF-induced Syk activation recruits Pyk2, which in turn recruits Grb2, leading to MAPK activation. TNF has also been shown to activate c-Raf-1 kinase (50,51). The sequential interaction of TNFR1, Syk, Grb2, SOS, Ras, and Raf-1 kinase can lead to MAPK activation.…”

Section: Discussionmentioning

confidence: 99%

TNF Activates Syk Protein Tyrosine Kinase Leading to TNF-Induced MAPK Activation, NF-κB Activation, and Apoptosis

Takada

Aggarwal

2004

The Journal of Immunology

108

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Spleen tyrosine kinase (Syk), a nonreceptor protein kinase initially found to be expressed only in hemopoietic cells, has now been shown to be expressed in nonhemopoietic cells and to mediate signaling of various cytokines. Whether Syk plays any role in TNF signaling was investigated. Treatment of Jurkat T cells with TNF activated Syk kinase but not ZAP70, another member of Syk kinase family, and the optimum activation occurred at 10 s and with 1 nM TNF. TNF also activated Syk in myeloid and epithelial cells. TNF-induced Syk activation was abolished by piceatannol (Syk-selective inhibitor), which led to the suppression of TNF-induced activation of c- JNK, p38 MAPK, and p44/p42 MAPK. Jurkat cells that did not express Syk (JCaM1, JCaM1/lck) showed lack of TNF-induced Syk, JNK, p38 MAPK, and p44/p42 MAPK activation, as well as TNF-induced IκBα phosphorylation, IκBα degradation, and NF-κB activation. TNF-induced NF-κB activation was enhanced by overexpression of Syk by Syk-cDNA and suppressed when Syk expression was down-regulated by expression of Syk-small interfering RNA (siRNA-Syk). The apoptotic effects of TNF were reduced by up-regulation of NF-κB by Syk-cDNA, and enhanced by down-regulation of NF-κB by siRNA-Syk. Immunoprecipitation of cells with Syk Abs showed TNF-dependent association of Syk with both TNFR1 and TNFR2; this association was enhanced by up-regulation of Syk expression with Syk-cDNA and suppressed by down-regulation of Syk using siRNA-Syk. Overall, our results demonstrate that Syk activation plays an essential role in TNF-induced activation of JNK, p38 MAPK, p44/p42 MAPK, NF-κB, and apoptosis.

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“…21 Other investigators have suggested that another lipid second messenger, ceramide, may also be able to play a role in Raf-1 activation, 22,23 although this is disputed. 24,25 Data from the laboratories of Sturgill, Morrison, and Marshall have suggested that protein serine/threonine and tyrosine phosphorylations play a role increasing Raf-1 activity when in the plasma membrane environment. [26][27][28] Several other studies have also suggested that PKC (protein kinase C) isoforms can directly regulate Raf-1 activity.…”

Section: Introduction: Map Kinase Historical Backgroundmentioning

confidence: 99%

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

et al. 1998

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During the last 10 years, multiple signal transduction pathways within cells have been discovered. These pathways have been linked to the regulation of many diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the many roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway. Recent evidence suggests that signaling by the MAP kinase pathway can both enhance proliferation by increased expression of molecules such as cyclin D1, but also cause growth arrest by increased expression of molecules such as the cyclin kinase inhibitor protein p21 Cip-1/MDA6/WAF1 . These differential effects on growth have been correlated to the amplitude and duration of the MAP kinase activity signal. Furthermore several laboratories are reporting data suggesting that inhibition of the MAP kinase pathway, as well as a family of upstream MAP kinase activators, the protein kinase C family, represent an important route to both radio-and chemo-sensitization of tumor cells. Herein, we describe the historical discovery and characterization of the MAP kinase pathway. In addition we describe potential mechanisms by which inhibition of protein kinase C, the MAP kinase pathway, and potentially of p21 Cip-1/MDA6/WAF1 expression, may alter the sensitivities of leukemic and carcinoma cells to cytotoxic insults, leading to increased apoptosis and loss of clonogenicity.

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Regulation of Raf-1 kinase by TNF via its second messenger ceramide and cross-talk with mitogenic signalling

Cited by 104 publications

References 64 publications

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

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

TNF Activates Syk Protein Tyrosine Kinase Leading to TNF-Induced MAPK Activation, NF-κB Activation, and Apoptosis

The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity

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