Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Xia, Zhengui; Dickens, Martin; Raingeaud, Joël; Davis, Roger J.; Greenberg, Michael E.

doi:10.1126/science.270.5240.1326

Cited by 5,072 publications

(4,235 citation statements)

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“…Concurrent activation of SAPK or p38 together with inhibition of Erks seem to be necessary for apoptosis following NGF withdrawal (Xia et al, 1995 (Figure 2a, upper panel).…”

Section: Resultsmentioning

confidence: 99%

“…However, two signalling pathways have recently been implicated in survival signalling by tyrosine kinase receptors: the classic Raf/MAPK pathway in the PC12 cell system (Xia et al, 1995) and the PI3-kinase pathway in PC12 cells and in ®broblasts Cooper, 1995, 1996). Both, the MAPK and the PI3-kinase pathways seem to be required for IGF-I to inhibit apoptosis of di erentiated PC12 cells following NGF withdrawal (Parrizas et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

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“…Concurrent activation of SAPK or p38 together with inhibition of Erks seem to be necessary for apoptosis following NGF withdrawal (Xia et al, 1995 (Figure 2a, upper panel).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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“…On the other hand, several groups have also reported that activation of the JNK/SAPK pathway can also induce cell death. For example, activation of JNK/SAPK in the absence of ERK activity induces apoptosis in neural cells (Xia et al, 1995). Furthermore, expression of MEKK1, an upstream activator of JNK/SAPK results in the apoptotic death of ®broblasts , suggesting that under some circumstances, JNK/SAPK signalling alone may be su cient to cause cell death.…”

Section: Discussionmentioning

confidence: 99%

The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway

et al. 1999

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“…c-jun luciferase activity Cerebellar granule neurons were transfected on the fifth day of culture (day in vitro (DIV) 5) by a modified calcium phosphate protocol (Xia et al 1995). Cells were washed with K25 ) S and calcium phosphate/DNA complexes were added to neurons for 1 h. Neurons were then washed twice with K25 ) S and restored to K25 + S medium.…”

Section: Immunoblottingmentioning

confidence: 99%

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mM potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. Neuronal survival is controlled in vivo by both retrograde signaling from neuronal targets as well as anterogradely via synaptic input. Cerebellar granule neurons are one such population whose survival is regulated by retrograde and anterograde signaling both in vivo and in vitro. In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al. 2000). These findings have been mimicked in vitro. Target-derived neurotrophic factors such as brain-derived growth factor (BDNF) and insulin-like growth factor (IGF)-1 promote the survival of cerebellar granule cells (Lindholm et al. 1993;Miller et al. 1997b). These neurons also undergo massive cell death when deafferentation is mimicked by removing the survival stimulus provided by depolarizing levels of potassium (Gallo et al. 1987). Abbreviations used: ASK, apoptosis signal regulating kinase 1; BAF, boc-aspartyl(OMe)-fluoromethylketone; BME, b-mercaptoethanol; CMV, cytomegalovirus; DEVD-amc, DEVD-aminomethylcoumarin; DIV, days in vitro; DTT, dithiothreitol; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; JNKKK, JNK kinase kinase; K5 ) S, buffer containing 5 mM KCl without serum; K25 + S, buf...

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Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Cited by 5,072 publications

References 76 publications

Specific TrkA survival signals interfere with different apoptotic pathways

Specific TrkA survival signals interfere with different apoptotic pathways

The oncogenic TEL/PDGFRβ fusion protein induces cell death through JNK/SAPK pathway

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

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