Activation‐independent nuclear translocation of mitogen activated protein kinase ERK1 mediated by thiol‐modifying chemicals

Meili, Ruedi; Ballmer-Hofer, Kurt

doi:10.1016/0014-5793(96)00927-1

Cited by 6 publications

(4 citation statements)

References 38 publications

(30 reference statements)

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“…Therefore, when protein degradation is inhibited, it seems that MAPK nuclear retention occurs independently of MAPK-dependent phosphorylating events. Interestingly, the only reported case where p42/p44 MAPK nuclear translocation can occur regardless of its activation was in REF52 cells treated with thiol-modifying agents such as phenylarsine oxide and N -ethylmaleimide ( 31 ). Considering that N -ethylmaleimide is known to inhibit one peptidase activity of the proteasome by acting on a critical cysteinyl residue ( 11 , 22 ), this agent could trigger, in some cells, the nuclear accumulation of p42/p44 MAPK by blocking the degradation of MAPK nuclear anchors.…”

Section: Discussionmentioning

confidence: 99%

Growth Factor–induced p42/p44 MAPK Nuclear Translocation and Retention Requires Both MAPK Activation and Neosynthesis of Nuclear Anchoring Proteins

Lenormand

Brondello

Brunet

et al. 1998

The Journal of Cell Biology

192

153

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Mitogen-activated protein kinases (p42/p44 MAPK, also called Erk2 and Erk1) are key mediators of signal transduction from the cell surface to the nucleus. We have previously shown that the activation of p42/p44 MAPK required for transduction of mitogenic signaling is associated with a rapid nuclear translocation of these kinases. However, the means by which p42 and p44 MAPK translocate into the nucleus after cytoplasmic activation is still not understood and cannot simply be deduced from their protein sequences. In this study, we have demonstrated that activation of the p42/ p44 MAPK pathway was necessary and sufficient for triggering nuclear translocation of p42 and p44 MAPK. First, addition of the MEK inhibitor PD 98059, which blocks activation of the p42/p44 MAPK pathway, impedes the nuclear accumulation, whereas direct activation of the p42/p44 MAPK pathway by the chimera ΔRaf-1:ER is sufficient to promote nuclear accumulation of p42/p44 MAPK. In addition, we have shown that this nuclear accumulation of p42/p44 MAPK required the neosynthesis of short-lived proteins. Indeed, inhibitors of protein synthesis abrogate nuclear accumulation in response to serum and accelerate p42/p44 MAPK nuclear efflux under conditions of persistent p42/p44 MAPK activation. In contrast, inhibition of targeted proteolysis by the proteasome synergistically potentiated p42/p44 MAPK nuclear localization by nonmitogenic agonists and markedly prolonged nuclear localization of p42/p44 MAPK after mitogenic stimulation. We therefore conclude that the MAPK nuclear translocation requires both activation of the p42/p44 MAPK module and neosynthesis of short-lived proteins that we postulate to be nuclear anchors.

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Section: Discussionmentioning

confidence: 99%

Growth Factor–induced p42/p44 MAPK Nuclear Translocation and Retention Requires Both MAPK Activation and Neosynthesis of Nuclear Anchoring Proteins

Lenormand

Brondello

Brunet

et al. 1998

The Journal of Cell Biology

192

153

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“…Several processes have been proposed to regulate this translocation, including phosphorylation and homodimerization of ERK1/2 (61); association with nuclear anchor proteins (62); and association in the cytoplasm with their upstream kinase activators, MEK1 and MEK2 (43), or with other cytoplasmic anchor proteins (63). Our results showing that coexpression of PTP-SL and ERK2 in COS-7 cells results in ERK2 retention in the cytoplasm favors the hypothesis of cytoplasmic retention as a major regulatory mechanism of ERK1/2 nuclear translocation.…”

mentioning

confidence: 99%

Interaction of Mitogen-activated Protein Kinases with the Kinase Interaction Motif of the Tyrosine Phosphatase PTP-SL Provides Substrate Specificity and Retains ERK2 in the Cytoplasm

Zúñiga¹,

Torres²,

Úbeda³

et al. 1999

Journal of Biological Chemistry

119

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ERK1 and ERK2 associate with the tyrosine phosphatase PTP-SL through a kinase interaction motif (KIM) located in the juxtamembrane region of PTP-SL. A glutathione S-transferase (GST)-PTP-SL fusion protein containing the KIM associated with ERK1 and ERK2 as well as with p38/HOG, but not with the related JNK1 kinase or with protein kinase A or C. Accordingly, ERK2 showed in vitro substrate specificity to phosphorylate GST-PTP-SL in comparison with GST-c-Jun. Furthermore, tyrosine dephosphorylation of ERK2 by the PTP-SL⌬KIM mutant was impaired. The in vitro association of ERK1/2 with GST-PTP-SL was highly stable; however, low concentrations of nucleotides partially dissociated the ERK1/2⅐PTP-SL complex. Partial deletions of the KIM abrogated the association of PTP-SL with ERK1/2, indicating that KIM integrity is required for interaction. Amino acid substitution analysis revealed that Arg and Leu residues within the KIM are essential for the interaction and suggested a regulatory role for Ser 231 . Finally, coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention of ERK2 in the cytoplasm in a KIM-dependent manner. Our results demonstrate that the noncatalytic region of PTP-SL associates with mitogen-activated protein kinases with high affinity and specificity, providing a mechanism for substrate specificity, and suggest a role for PTP-SL in the regulation of mitogen-activated protein kinase translocation to the nucleus upon activation. Extracellular signal-regulated kinases (ERKs)1 are serine/ threonine kinases of the MAP kinase family that are activated by a variety of growth and differentiation factors (1-4). ERK1/ 2-related kinases include members of the stress-and inflammation-activated MAP kinase subgroups, JNK/stress-activated protein kinase and p38/HOG (5-8). Differences in the response of ERK1/2 to activation agents have been postulated to account for the cell type-and stimulus-specific adaptive responses mediated by these kinases (9). For instance, inhibition of ERK1/2 function prevents proliferation of Chinese hamster ovary fibroblasts in response to growth-stimulating agents (10), and constitutive activation of the ERK1/2 pathway induces transformation of 3T3 fibroblasts (11,12). On the other hand, ERK1 and ERK2 also mediate the inhibition of cell growth arrest induced by nerve growth factor in 3T3 cells (13), and the differentiation of neuronal PC12 or erythroleukemia K562 cells is blocked by inhibition of the ERK1/2 pathway (11,14,15). Cytoplasmic activation of ERK1/2 requires the phosphorylation of both tyrosine and threonine regulatory residues, which is accomplished by the dual-specificity kinases MEK1 and MEK2 (16). Upon activation, ERK1 and ERK2 phosphorylate cytosolic and membrane-bound proteins, including signal transduction molecules and cytoskeletal components (1, 2). In addition, after stimulus-induced translocation to the nucleus, ERK1 and ERK2 phosphorylate and regulate the function of several transcription factors, thereby controlling the expression of specific responsive ge...

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“…We next tested whether (1-313)-GFP aggregated as an insoluble form in the cytoplasm. The cells transfected with (1-313)-GFP were treated with 40 M of phenylarsine oxide, which is known to induce nuclear translocation of ERK1 without its activation (25). As shown in Fig.…”

Section: Fig 1 Localization Of Erk2-gfp and Its Deletion Mutants Inmentioning

confidence: 99%

Identification of a C-terminal Region That Is Required for the Nuclear Translocation of ERK2 by Passive Diffusion

Shibayama

Shibata-Seita

Miura

et al. 2002

Journal of Biological Chemistry

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Extracellular signal-regulated kinase 2 (ERK2) is located in the cytoplasm of resting cells and translocates into the nucleus upon extracellular stimuli by active transport of a dimer. Passive transport of an ERK2 monomer through the nuclear pore is also reported to coexist. We attempted to characterize the cytoplasmic retention and nuclear translocation of fusion proteins between deletion and site-directed mutants of ERK2 and green fluorescent protein (GFP). The overexpressed ERK2-GFP fusion protein is usually localized to both the cytoplasm and the nucleus unless a cytoplasmic anchoring protein is coexpressed. Deletion of 45 residues, but not 43 residues, from the C terminus of ERK2 prevented the nuclear distribution of the ERK2-GFP fusion protein. Substitution of a part of residues 299 -313 to alanine residues also prevented the nuclear distribution of the ERK2-GFP fusion protein without abrogation of its nuclear active transport. These observations may indicate that the passive diffusion of ERK2 into the nucleus is not simple diffusion but includes a specific interaction process between residues 299 -313 and the nuclear pore complex and that this interaction is not required for the active transport. We also showed that substitution of Tyr 314 to alanine residue abrogated the cytoplasmic retention of the ERK2-GFP fusion protein by PTP-SL but not by MEK1. Mitogen-activated protein kinase (MAPK)1 pathways include a family of protein serine/threonine kinases that are activated by a wide variety of extracellular stimuli, such as growth factors, hormones, cytokines, and cellular stresses (1, 2). Extracellular signal-regulated kinases 1 and 2 (ERK1/2), also known as p44/p42 MAPK, are well studied members of this family, and it is known that they preferentially regulate cell growth and differentiation. Upon stimulation, ERKs are activated via a cascade of phosphorylation and activation of the protein kinases Raf-1 and MAPK/ERK kinase (MEK). Activated MEK, which is specific to ERKs, activates ERKs by catalyzing the phosphorylation of ERKs on both a threonine and a tyrosine residue. The activated ERKs can phosphorylate a variety of substrates, including transcription factors that control cellular growth, such as Elk-1.In resting cells, ERKs are primarily localized to the cytoplasm. Upon extracellular stimulation, a fraction of cytoplasmic ERKs translocate into the nucleus (3). The dissociation of ERK2 from its cytoplasmic anchor is induced by the phosphorylation of ERK2 at Tyr (and Thr) (4 -6). Phosphorylated ERK2 forms a homodimer and translocates into the nucleus (5-7). Because ERK2 does not have a clear nuclear localization signal, it is hypothesized that this dimerization provokes the nuclear localization signal. However, the nuclear translocation mechanism of ERK2 still remains to be clarified. Nucleartransported ERK2 is dephosphorylated and exported to the cytosol by a Crm1-dependent mechanism that involves MEK1 (8). Adachi et al. (6) have demonstrated that there is another nuclear import system of ERK2 differe...

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Activation‐independent nuclear translocation of mitogen activated protein kinase ERK1 mediated by thiol‐modifying chemicals

Cited by 6 publications

References 38 publications

Growth Factor–induced p42/p44 MAPK Nuclear Translocation and Retention Requires Both MAPK Activation and Neosynthesis of Nuclear Anchoring Proteins

Growth Factor–induced p42/p44 MAPK Nuclear Translocation and Retention Requires Both MAPK Activation and Neosynthesis of Nuclear Anchoring Proteins

Interaction of Mitogen-activated Protein Kinases with the Kinase Interaction Motif of the Tyrosine Phosphatase PTP-SL Provides Substrate Specificity and Retains ERK2 in the Cytoplasm

Identification of a C-terminal Region That Is Required for the Nuclear Translocation of ERK2 by Passive Diffusion

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