Nuclear Entry of Activated MAPK Is Restricted in Primary Ovarian and Mammary Epithelial Cells

Smith, Elizabeth; Cai, Kathy Q.; Smedberg, Jennifer L.; Ribeiro, Melina M.; Rula, Malgorzata E.; Slater, Carolyn; Godwin, Andrew K.; Xu, Xiang Xi

doi:10.1371/journal.pone.0009295

Cited by 33 publications

(31 citation statements)

References 53 publications

(78 reference statements)

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“…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). All of these mechanisms are likely to play important roles in governing the specificity and efficiency of ERK signaling in health and disease.…”

Section: Discussionmentioning

confidence: 90%

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: 90%

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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“…This is an encouraging result that may suggest that the EPE peptide may have a good therapeutic window by affecting only the cancer but not the surrounding cells. The molecular mechanism that causes this resistance of non-transformed cells is likely dependent on the smaller number of nuclear pores and importins, which results in a slower kinetic of nuclear translocation 33 , and thereby probably a lower susceptibility to inhibition of translocation.…”

Section: Discussionmentioning

confidence: 99%

The nuclear translocation of ERK1/2 as an anticancer target

et al. 2015

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A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non-transformed, immortalized cells. It even inhibits the viability of PLX4032-and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers.

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“…We previously showed that Kpnb1 mRNA and protein are expressed at elevated levels in cervical tumors and cervical cancer cell lines (6), and that the promoter is more highly active in cervical cancer cells due to its activation by the cell-cycle regulator, E2F (7). Smith and colleagues (2010) found that Kpnb1 mRNA was elevated in ovarian cancer cell lines and transformed ovarian cells (8) and Kuusisto and colleagues (2011) also described increased levels of Kpnb1 in several transformed cell lines (9). These lines of evidence suggest that the Kpnb1 protein is associated with cellular transformation and cancer.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

Watt

Chi

Stelma

et al. 2016

Molecular Cancer Therapeutics

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Karyopherin beta 1 (Kpnb1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnb1 expression was found in certain cancers and Kpnb1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnb1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnb1 and Inhibitor of Nuclear Import-43, INI-43

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Nuclear Entry of Activated MAPK Is Restricted in Primary Ovarian and Mammary Epithelial Cells

Cited by 33 publications

References 53 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 nuclear translocation of ERK1/2 as an anticancer target

Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic

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