The Mitogen-Activated Protein Kinase Scaffold KSR1 Is Required for Recruitment of Extracellular Signal-Regulated Kinase to the Immunological Synapse

ABSTRACT KSR1 is a mitogen-activated protein (MAP) kinase scaffold that enhances the activation of the MAP kinase extracellular signal-regulated kinase (ERK). The function of KSR1 in NK cell function is not known. Here we show that KSR1 is required for efficient NK-mediated cytolysis and polarization of cytolytic granules. Single-cell analysis showed that ERK is activated in an all-or-none fashion in both wild-type and KSR1-deficient cells. In the absence of KSR1, however, the efficiency of ERK activation is attenuated. Imaging studies showed that KSR1 is recruited to the immunological synapse during T-cell activation and that membrane recruitment of KSR1 is required for recruitment of active ERK to the synapse.

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Negative regulation of mTOR activation by diacylglycerol kinases

Blood ◽

10.1182/blood-2010-08-300731 ◽

2011 ◽

Vol 117 (15) ◽

pp. 4022-4031 ◽

Cited By ~ 70

Author(s):

Balachandra K. Gorentla ◽

Chi-Keung Wan ◽

Xiao-Ping Zhong

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Mitogen Activated Protein Kinase ◽

Effector Memory ◽

Multiple Characteristic ◽

Genetic Ablation ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Constitutively Active

Abstract The engagement of TCR induces T-cell activation, which initiates multiple characteristic changes such as increase in cell size, cell division, and the production of cytokines and other effector molecules. The mammalian target of rapamycin (mTOR) regulates protein synthesis, transcription, cell survival, and autophagy. Critical roles of mTOR in T-cell activation and effector/memory differentiation have been revealed using chemical inhibitors or by genetic ablation of mTOR in T cells. However, the connection between mTOR signaling and other signaling cascades downstream of TCR is unclear. We demonstrate that diacylglycerol (DAG) and TCR engagement activate signaling in both mTOR complexes 1 and 2 through the activation of the Ras–mitogen-activated protein kinase/extracellular signal–regulated kinase 1/2 (Mek1/2)–extracellular signal–regulated kinase 1/2 (Erk1/2)–activator protein 1 (AP-1), known collectively as the Ras-Mek1/2-Erk1/2-AP-1 pathway. Deficiency of RasGRP1 or inhibition of Mek1/2 activity drastically decreases TCR-induced mTOR activation, whereas constitutively active Ras or Mek1 promotes mTOR activation. Although constitutively active Akt promotes TCR-induced mTOR activation, such activation is attenuated by Mek1/2 inhibition. We demonstrated further that DAG kinases (DGKs) α and ζ, which terminate DAG-mediated signaling, synergistically inhibit TCR-induced mTOR activation by inhibiting the Ras-Mek1/2-Erk/12 pathway. These observations provide novel insights into the regulation of mTOR activation.

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p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

Molecular Biology of the Cell ◽

10.1091/mbc.e03-08-0592 ◽

2004 ◽

Vol 15 (2) ◽

pp. 922-933 ◽

Cited By ~ 171

Author(s):

Almudena Porras ◽

Susana Zuluaga ◽

Emma Black ◽

Amparo Valladares ◽

Alberto M. Alvarez ◽

...

Keyword(s):

Map Kinase ◽

Cell Types ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Survival Pathways ◽

Proapoptotic Protein ◽

Extracellular Signal ◽

Survival Pathway ◽

Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

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The Role of the p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and Phosphoinositide-3-OH Kinase Signal Transduction Pathways in CD40 Ligand-Induced Dendritic Cell Activation and Expansion of Virus-Specific CD8+T Cell Memory Responses

The Journal of Immunology ◽

10.4049/jimmunol.172.10.6047 ◽

2004 ◽

Vol 172 (10) ◽

pp. 6047-6056 ◽

Cited By ~ 71

Author(s):

Qigui Yu ◽

Colin Kovacs ◽

Feng Yun Yue ◽

Mario A. Ostrowski

Keyword(s):

Cell Activation ◽

Cd40 Ligand ◽

Mitogen Activated Protein Kinase ◽

T Cell Memory ◽

Dendritic Cell Activation ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Cd8 T Cell Memory

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Faculty Opinions recommendation of Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1006218.77810 ◽

2002 ◽

Author(s):

Angel Nebreda

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Premature Senescence ◽

Extracellular Signal Regulated Kinase ◽

Oncogenic Ras ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Sequential Activation

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ERK5 and its role in tumour development

Biochemical Society Transactions ◽

10.1042/bst20110663 ◽

2012 ◽

Vol 40 (1) ◽

pp. 251-256 ◽

Cited By ~ 50

Author(s):

Pamela A. Lochhead ◽

Rebecca Gilley ◽

Simon J. Cook

Keyword(s):

Mitogen Activated Protein Kinase ◽

Invasion And Migration ◽

Extracellular Signal Regulated Kinase ◽

Protein Levels ◽

Extracellular Signal ◽

Mapk Signalling ◽

Mitogen Activated Protein ◽

Tumour Cell Invasion ◽

And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

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