Dual phosphorylation and autophosphorylation in mitogen-activated protein (MAP) kinase activation

Her, Jeng-Horng; Lakhani, Sunil R.; Zu, Kai; Vila, Jordi; Dent, Paul; Sturgill, Thomas W.; Weber, Michael J.

doi:10.1042/bj2960025

Cited by 115 publications

(80 citation statements)

References 40 publications

(59 reference statements)

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“…Plasmid pEGFP-F was purchased from Clontech (Palo Alto, CA, USA). pCEP, K79M (a MEK1/ 2 ATP binding mutant), TEYE (with glutamic acids substituted at T183 and Y185), and K52R (an ERK2 ATP binding mutant) plasmids 16 were generously donated by Melanie Cobb, University of Texas Southwestern Medical Center, Dallas, TX, USA.…”

Section: Methodsmentioning

confidence: 99%

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Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Brognard

Dennis

2002

Cell Death Differ

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To evaluate the role of the MEK/ERK pathway in NSCLC survival, we analyzed NSCLC cell lines that differed in tumor histology and status of p53, Rb, and K-ras. Constitutive ERK1/2 activity was demonstrated in 17 of 19 cell lines by maintenance of ERK1/2 phosphorylation with serum deprivation. Phosphorylation of ERK1/2 correlated with phosphorylation of MEK1/2 and p90RSK, but was inversely correlated with phosphorylation of c-Raf at S259. With serum deprivation, the MEK inhibitors, PD98059 and U0126, inhibited ERK1/2 activity but did not increase apoptosis. PD98059 and U0126 induced cell cycle arrest in G 0 /G i in cells with the highest levels of ERK1/2 activity, which correlated with induction of p27 but not p21. To confirm the cytostatic response to MEK inhibitors, we performed transient transfections with dominant negative forms of MEK or ERK. Surprisingly, dominant negative MEK and ERK mutants increased apoptosis without affecting cell cycle or p27 levels. When combined with paclitaxel, MEK inhibitors had no effect on apoptosis. In contrast, dominant negative ERK2 potentiated paclitaxel-induced apoptosis. Our studies show that constitutive ERK1/2 activity in NSCLC cells promotes cellular survival and chemotherapeutic resistance. Moreover, our data are the first to demonstrate divergent cellular responses to inhibition of the MEK/ERK pathway by small molecule inhibitors or dominant negative mutants.

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Section: Methodsmentioning

confidence: 99%

“…16 TEYE has glutamic acids substituted at T183 and Y185. Similar sites exist within the activation domain of ERK1 (T202 and Y204), where ERK1 and ERK2 are over 90% similar and the immediate surrounding amino acids are identical.…”

Section: Dominant Negative Mutants Cause Apoptosis Without Cell Cyclementioning

confidence: 99%

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Brognard

Dennis

2002

Cell Death Differ

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“…To do this we used a combination of techniques, including assessment of MAP kinase activity by Western blot analysis of the dual phosphorylation (Thr 183 /Tyr 185 ) status of Erk1 and Erk2 (22,23) and measurement of the in vitro kinase activities of anti-Erk2 immune complexes (9). We also probed the Erk2-containing immune complexes for expression of associated MAP kinase phosphatases such as Pac-1 and, in addition, the Ser/Thr phosphatase PP2A, which has also been reported to modulate ErkMAP kinase activity (20,24).…”

Section: Pre-exposure To Es-62 Primes the Bcr-mediated Recruitment Anmentioning

confidence: 99%

A Filarial Nematode-Secreted Phosphorylcholine-Containing Glycoprotein Uncouples the B Cell Antigen Receptor from Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase by Promoting the Surface Ig-Mediated Recruitment of Src Homology 2 Domain-Containing Tyrosine Phosphatase-1 and Pac-1 Mitogen-Activated Kinase-Phosphatase

Deehan

Harnett

2001

The Journal of Immunology

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Unraveling the molecular mechanisms by which filarial nematodes, major human pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62), a homologue of phosphorylcholine-containing molecules that are secreted by human parasites and which is active in rodent models of filarial infection, is able to polyclonally activate certain protein tyrosine kinase and mitogen-activating protein kinase signal transduction elements in B lymphocytes. Such activation mediates desensitization of subsequent B cell Ag receptor (BCR) ligation-induced activation of extracellular signal-regulated kinase-mitogen-activated protein (ErkMAP) kinase and ultimately B cell proliferation. We now show that the desensitization is due to ES-62 targeting two major regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 primes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Igαβ-ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinase signaling in ES-62-primed B cells is terminated by the MAP kinase phosphatase, Pac-1 that is activated consequently to challenge via the BCR.

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“…The Erk cascade is stimulated by extracellular stimuli and the kinase is activated when dually phosphorylated at the TEY motif by the upstream kinase, mitogen-activated protein kinase kinase (MEK) (Payne et al 1991;Her et al 1993). PD098059, a cell-permeable inhibitor of MEK, can effectively block the Erk cascade (Alessi et al 1995) and has been extensively used to examine the role of Erk in vivo.…”

mentioning

confidence: 99%

Extracellular Signal-Regulated Kinase Activity in the Entorhinal Cortex Is Necessary for Long-Term Spatial Memory

Slee¹,

Dash²

2002

Learn. Mem.

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Lesion studies have provided evidence that the entorhinal cortex (EC) participates in spatial memory. However, the molecular cascades that underlie memory-associated changes in the EC and its specific role in spatial memory, however, have not been clearly delineated. Recently, it has been shown that activation of extracellular signal-regulated kinase (Erk, a mitogen-activated protein kinase family member) in the dorsal hippocampus is necessary for spatial memory. To examine whether similar mechanisms are used for spatial memory storage in the EC, Erk activity was inhibited after training in the Morris water maze. Bilateral infusion of the mitogen-activated protein kinase kinase inhibitor PD098059 into the EC immediately after training resulted in a memory deficit observed during a retention test performed 48 h later. This deficit was abolished with pretraining in a different water maze in which animals were able to learn the general task requirements and the appropriate search strategies. The absence of a deficit indicates that Erk activity in the EC may be involved in storing the task requirements or the search strategies. The findings presented in this article are consistent with the idea that the EC is involved in spatial memory and indicate that Erk activity is necessary for memory consolidation in this structure.

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Dual phosphorylation and autophosphorylation in mitogen-activated protein (MAP) kinase activation

Cited by 115 publications

References 40 publications

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants

Extracellular Signal-Regulated Kinase Activity in the Entorhinal Cortex Is Necessary for Long-Term Spatial Memory

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