Extracellular‐regulated kinase—mitogen‐activated protein kinase cascade: Unsolved issues

Bodart, Jean‐François

doi:10.1002/jcb.22477

Cited by 36 publications

(34 citation statements)

References 47 publications

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“…Upon stimulation, phosphorylation of the ERK TEY domain releases ERK and allows phosphorylation of its NTS by CK2 and active ERK to generate a negatively charged patch in ERK, binding to importin 7 and nuclear translocation. These results provide an important role of CK2 in regulating nuclear ERK activities.Extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are central signaling proteins that mediate a variety of vital cellular processes, including proliferation, survival, and even apoptosis (1,4,15,29,50). In order to execute their functions, ERK molecules activate a large number of regulatory proteins, which are localized either in the cytoplasm or within various organelles, including mainly the nucleus (52).…”

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confidence: 99%

Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation

Plotnikov

Chuderland

Karamansha

et al. 2011

Molecular and Cellular Biology

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The extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase [MAPK] family. Upon stimulation, these kinases translocate from the cytoplasm to the nucleus, where they induce physiological processes such as proliferation and differentiation. The mechanism of translocation of this kinase involves phosphorylation of two Ser residues within a nuclear translocation signal (NTS), which allows binding to importin7 and a subsequent penetration via nuclear pores. Here we show that the phosphorylation of both Ser residues is mediated mainly by casein kinase 2 (CK2) and that active ERK may assist in the phosphorylation of the N-terminal Ser. We also demonstrate that the phosphorylation is dependent on the release of ERK from cytoplasmic anchoring proteins. Crystal structure of the phosphomimetic ERK revealed that the NTS phosphorylation creates an acidic patch in ERK. Our model is that in resting cells ERK is bound to cytoplasmic anchors, which prevent its NTS phosphorylation. Upon stimulation, phosphorylation of the ERK TEY domain releases ERK and allows phosphorylation of its NTS by CK2 and active ERK to generate a negatively charged patch in ERK, binding to importin 7 and nuclear translocation. These results provide an important role of CK2 in regulating nuclear ERK activities.Extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are central signaling proteins that mediate a variety of vital cellular processes, including proliferation, survival, and even apoptosis (1,4,15,29,50). In order to execute their functions, ERK molecules activate a large number of regulatory proteins, which are localized either in the cytoplasm or within various organelles, including mainly the nucleus (52). Indeed, the number of nuclear targets and downstream effectors of ERK, including a variety of transcription factors (17), is well over 100. These direct and indirect targets participate in the regulation of transcription as well as chromatin remodeling, and therefore they play a central role in mediating essentially all stimulated cellular processes (29). Moreover, because these ERK-induced nuclear activities are such central signaling processes, their dysregulation often leads to severe pathological processes, including oncogenic transformation, neurodegenerative diseases, and developmental diseases (15). In order to transmit their nuclear signals, ERK molecules that are localized in the cytoplasm of quiescent cells rapidly translocate into the nucleus upon stimulation. Although many details on ERK in the nucleus were already provided, the mechanisms of its translocation are not fully worked out yet.The nucleus is separated from the cytoplasm by a double membrane envelope (25). Nuclear shuttling of proteins occurs through a specialized nuclear pore complex (NPC), which ensures high selectivity of molecules for nuclear import/export, thus supporting proper cytoplasmic/nuclear molecular balance.

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confidence: 99%

Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation

Plotnikov

Chuderland

Karamansha

et al. 2011

Molecular and Cellular Biology

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“…The known substrate for MEK1/2 is ERK1/2 (7). The role of ERK activity during G 2 /M transition is not well understood, but ERK seems to function through a complex and indirect role on a small subset of G 2 /M phosphoproteins (55), and the downstream effectors of ERK, which are required for mitosis progression, remain to be determined (2). However, a specific inhibitor of ERK1/2 (FR180204) had no influence on the titers of either the passaged mutants or wild-type PrV.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Viral and Cellular Factors Influencing Herpesvirus-Induced Nuclear Envelope Breakdown

Grimm

Klupp

Granzow

et al. 2012

J Virol

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Herpesvirus nucleocapsids are translocated from their assembly site in the nucleus to the cytosol by acquisition of a primary envelope at the inner nuclear membrane which subsequently fuses with the outer nuclear membrane. This transport through the nuclear envelope requires homologs of the conserved herpesviral pUL31 and pUL34 proteins which form the nuclear egress complex (NEC). In its absence, 1,000-fold less virus progeny is produced. We isolated a UL34-negative mutant of the alphaherpesvirus pseudorabies virus (PrV), PrV-ΔUL34Pass, which regained replication competence after serial passages in cell culture by inducing nuclear envelope breakdown (NEBD) (B. G. Klupp, H. Granzow, and T. C. Mettenleiter, J. Virol. 85:8285–8292, 2011). To test whether this phenotype is unique, passaging experiments were repeated with a UL31 deletion mutant. After 60 passages, the resulting PrV-ΔUL31Pass replicated similarly to wild-type PrV. Ultrastructural analyses confirmed escape from the nucleus via NEBD, indicating an inherent genetic disposition in herpesviruses. To identify the mutated viral genes responsible for this phenotype, the genome of PrV-ΔUL34Pass was sequenced and compared to the genomes of parental PrV-Ka and PrV-ΔUL34. Targeted sequencing of PrV-ΔUL31Pass disclosed congruent mutations comprising genes encoding tegument proteins (pUL49, pUL46, pUL21, pUS2), envelope proteins (gI, pUS9), and protease pUL26. To investigate involvement of cellular pathways, different inhibitors of cellular kinases were tested. While induction of apoptosis or inhibition of caspases had no specific effect on the passaged mutants, roscovitine, a cyclin-dependent kinase inhibitor, and U0126, an inhibitor of MEK1/2, specifically impaired replication of the passaged mutants, indicating involvement of mitosis-related processes in herpesvirus-induced NEBD.

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“…Here, we first evaluated the effect of increased CD147 on the activation status of Ras in MCF-10A cells because Ras is frequently upstream of ERK activation (39). We found that up-regulation of CD147 led to a ϳ1.5-2-fold increase in Ras activation, measured as an increased proportion of Ras-bound GTP, as well as a concomitant increase in phosphorylated ERK (p-ERK) (Fig.…”

Section: Up-regulation Of Cd147 Induces Activation Of Egfr-ras-erk Simentioning

confidence: 99%

CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness

Grass

Tolliver

Bratoeva

et al. 2013

Journal of Biological Chemistry

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Background: CD147 induces invadopodia activity and invasiveness in breast epithelial cells. Results: CD147 forms complexes with CD44 and EGFR in lipid raftlike membrane domains and induces hyaluronan-CD44-dependent EGFR-Ras-ERK signaling that promotes invadopodia activity and invasiveness. Conclusion: CD147 induces signaling complexes critical to invasiveness in breast epithelial cells. Significance: CD147 is a potential therapeutic target and disease marker in breast cancer.

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Extracellular‐regulated kinase—mitogen‐activated protein kinase cascade: Unsolved issues

Cited by 36 publications

References 47 publications

Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation

Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation

Analysis of Viral and Cellular Factors Influencing Herpesvirus-Induced Nuclear Envelope Breakdown

CD147, CD44, and the Epidermal Growth Factor Receptor (EGFR) Signaling Pathway Cooperate to Regulate Breast Epithelial Cell Invasiveness

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