A New Paradigm for MAPK: Structural Interactions of hERK1 with Mitochondria in HeLa Cells

Galli, Soledad; Jahn, Olaf; Hitt, Reiner; Hesse, Doerte; Opitz, Lennart; Plessmann, Uwe; Urlaub, Henning; Poderoso, Juan José; Jares‐Erijman, Elizabeth A.; Jovin, Thomas M.

doi:10.1371/journal.pone.0007541

Cited by 47 publications

(52 citation statements)

References 69 publications

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“…Therefore, nuclear translocation of ERK is essential for the induction of many ERK-dependent processes, and indeed, specific abrogation of ERK nuclear translocation blocks the progression of proliferation and oncogenic transformation (2,10,44). It should be noted, however, that the nuclear activity is probably not sufficient to induce all ERKdependent processes, as their activity in the cytoplasm (5) and mitochondria (12) as well as ERK1c activity in the Golgi apparatus (37,38) is also necessary to induce proliferation and survival. Therefore, ERK translocation seems to be regulated by a variety of methods, such as cytoplasmic anchoring by interaction with specific proteins (7,16), changes in NPC's number in different cell types (40), interaction with Imp7 (21), and phosphorylation by CK2 (the study presented here).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…143 Another important step in understanding the mitochondrial localization, regulation, and role in mitochondrial activities was the recent proteomic study on ERK1/2-interacting proteins in the mitochondria. 96 In this study, it was demonstrated that ERK1 physically associates with structural, signaling, transport, and metabolic proteins in the mitochondria of HeLa cells. Among the new interactors identified were the voltage-dependent anion channel 1 (VDAC1) that may facilitate the mitochondrial transport of ERK1/2.…”

Section: Erk1/2 In the Mitochondriamentioning

confidence: 80%

“…The various translocation events and distinct localizations, which have important physiological functions, can be categorized into 2 main functional groups. The first is the ability of the translocated ERK1/2 to regulate specific activities within certain organelles, such as the regulation of transcription in the nucleus and mitochondria 22,96 or the regulation of mitotic Golgi fragmentation. 64 The second function is to bring components of the ERK1/2 cascade into proper localization in the outer surface of the organelles, where the signaling components phosphorylate specialized substrates without significant nuclear translocation.…”

Section: Localization Of Components Of the Erk1/2 Cascadementioning

confidence: 99%

“…97,98 As described above, scaffold and other interacting proteins often regulate the targeting to the organelles. Examples of such directing proteins are MP1 that directs ERK1 to endosomes, 99 VDAC to the mitochondria, 96 and Sef1 to the Golgi. 100 Cytoskeletal elements, as well as cytoskeleton-related proteins, may also participate in this effect.…”

Section: Localization Of Components Of the Erk1/2 Cascadementioning

confidence: 99%

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The ERK Cascade: Distinct Functions within Various Subcellular Organelles

2011

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The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is a central signaling pathway that regulates a wide variety of stimulated cellular processes, including mainly proliferation, differentiation, and survival, but apoptosis and stress response as well. The ability of this linear cascade to induce so many distinct and even opposing effects after various stimulations raises the question as to how the signaling specificity of the cascade is regulated. Over the past years, several specificity-mediating mechanisms have been elucidated, including temporal regulation, scaffolding interactions, crosstalks with other signaling components, substrate competition, and multiple components in each tier of the cascade. In addition, spatial regulation of various components of the cascade is probably one of the main ways by which signals can be directed to some downstream targets and not to others. In this review, we describe first the components of the ERK1/2 cascade and their mode of regulation by kinases, phosphatases, and scaffold proteins. In the second part, we focus on the role of MEK1/2 and ERK1/2 compartmentalization in the nucleus, mitochondria, endosomes, plasma membrane, cytoskeleton, and Golgi apparatus. We explain that this spatial distribution may direct ERK1/2 signals to regulate the organelles' activities. However, it can also direct the activity of the cascade's components to the outer surface of the organelles in order to bring them to close proximity to specific cytoplasmic targets. We conclude that the dynamic localization of the ERK1/2 cascade components is an important regulatory mechanism in determining the signaling specificity of the cascade, and its understanding should shed a new light on the understanding of many stimulus-dependent processes.

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“…Bands from 1D-SDS-PAGE gels or plugs from 2D-16-BAC/SDS-PAGE gels were subjected to tryptic in-gel digestion, and the released peptides were extracted in two consecutive steps with 0.5% trifluoroacetic acid (TFA)/10% acetonitrile and 0.5% TFA/50% acetonitrile, respectively. Pooled extracts were dried, redissolved in 0.1% TFA, and subjected to reversed phase separation on an Ultimate nano-HPLC system (Dionex) as described previously (Galli et al, 2009). Peptides were desalted and preconcentrated on a 2 cm ϫ 75 m column (packed in-house with Reprosil-Pur C 18 -AQ material of 5 m particle and 100 Å pore size; Dr. Maisch) with 0.1% TFA at a flow rate of 8 l/min.…”

Section: Methodsmentioning

confidence: 99%

Quantitative and Integrative Proteome Analysis of Peripheral Nerve Myelin Identifies Novel Myelin Proteins and Candidate Neuropathy Loci

Patzig¹,

Jahn²,

Tenzer³

et al. 2011

J. Neurosci.

158

190

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Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immunobased methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion protein. Finally, the systematic comparison of our compendium with the positions of human disease loci allowed us to identify several candidate genes for hereditary demyelinating neuropathies. These results illustrate how the integration of unbiased proteome, transcriptome, and genome data can contribute to a molecular dissection of the biogenesis, cell biology, metabolism, and pathology of myelin. Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia-axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relative abundance was previously misestimated due to technical limitations regarding protein separation and visualization. Focusing on tetraspan-transmembrane proteins, we validated novel myelin constituents using immuno-based methods. Bioinformatic comparison with mRNA-abundance profiles allowed the categorization in functional groups coregulated during myelin biogenesis and maturation. By differential myelin proteome analysis, we found that the abundance of septin 9, the protein affected in hereditary neuralgic amyotrophy, is strongly increased in a novel mouse model of demyelinating neuropathy caused by the loss of prion pr...

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A New Paradigm for MAPK: Structural Interactions of hERK1 with Mitochondria in HeLa Cells

Cited by 47 publications

References 69 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

The ERK Cascade: Distinct Functions within Various Subcellular Organelles

Quantitative and Integrative Proteome Analysis of Peripheral Nerve Myelin Identifies Novel Myelin Proteins and Candidate Neuropathy Loci

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