scholarly journals Integration of Protein Kinases mTOR and Extracellular Signal-Regulated Kinase 5 in Regulating Nucleocytoplasmic Localization of NFATc4

2008 ◽  
Vol 28 (10) ◽  
pp. 3489-3501 ◽  
Author(s):  
Teddy T. C. Yang ◽  
Raymond Y. L. Yu ◽  
Anissa Agadir ◽  
Guo-Jian Gao ◽  
Roberto Campos-Gonzalez ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Subcellular Distribution ◽  
Nuclear Export ◽  
Mitogen Activated Protein Kinase ◽  
Nucleocytoplasmic Shuttling ◽  
Tor Signaling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Gate Keeping

ABSTRACT The target of rapamycin (TOR) signaling regulates the nucleocytoplasmic shuttling of transcription factors in yeast. Whether the mammalian counterpart of TOR (mTOR) also regulates nucleocytoplasmic shuttling is not known. Using a phospho-specific monoclonal antibody, we demonstrate that mTOR phosphorylates Ser168,170 of endogenous NFATc4, which are conserved gate-keeping Ser residues that control NFAT subcellular distribution. The mTOR acts as a basal kinase during the resting state to maintain NFATc4 in the cytosol. Inactivation and nuclear export of NFATc4 are mediated by rephosphorylation of Ser168,170, which can be a nuclear event. Kinetic analyses demonstrate that rephosphorylation of Ser168,170 of endogenous NFATc4 is mediated by mTOR and, surprisingly, by extracellular signal-regulated kinase 5 (ERK5) mitogen-activated protein kinase as well. Ablation of ERK5 in the Erk5 −/− cells ascertains defects in NFATc4 rephosphorylation and nucleocytoplasmic shuttling. In addition, phosphorylation of NFATc4 by ERK5 primes subsequent phosphorylation mediated by CK1α. These results demonstrate that distinct protein kinases are integrated to phosphorylate the gate-keeping residues Ser168,170 of NFATc4, to regulate subcellular distribution. These data also expand the repertoire of physiological substrates of mTOR and ERK5.

scholarly journals Regulation of Nuclear Translocation of Extracellular Signal-Regulated Kinase 5 by Active Nuclear Import and Export Mechanisms

2006 ◽  
Vol 26 (5) ◽  
pp. 1679-1690 ◽  
Author(s):  
Kunio Kondoh ◽  
Kazuya Terasawa ◽  
Hiroko Morimoto ◽  
Eisuke Nishida
Keyword(s):  
Nuclear Import ◽  
Nuclear Export ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Nucleocytoplasmic Shuttling ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, plays an important role in growth factor signaling to the nucleus. However, molecular mechanisms regulating subcellular localization of ERK5 have remained unclear. Here, we show that nucleocytoplasmic shuttling of ERK5 is regulated by a bipartite nuclear localization signal-dependent nuclear import mechanism and a CRM1-dependent nuclear export mechanism. Our results show that the N-terminal half of ERK5 binds to the C-terminal half and that this binding is necessary for nuclear export of ERK5. They further show that the activating phosphorylation of ERK5 by MEK5 results in the dissociation of the binding between the N- and C-terminal halves and thus inhibits nuclear export of ERK5, causing its nuclear import. These results reveal the mechanism by which the activating phosphorylation of ERK5 induces its nuclear import and suggest a novel example of a phosphorylation-dependent control mechanism for nucleocytoplasmic shuttling of proteins.

scholarly journals mTORC2 Is Involved in the Induction of RSK Phosphorylation by Serum or Nutrient Starvation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1567
Author(s):  
Po-Chien Chou ◽  
Swati Rajput ◽  
Xiaoyun Zhao ◽  
Chadni Patel ◽  
Danielle Albaciete ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
S6 Kinase ◽  
Agc Kinases ◽  
Extracellular Signal Regulated Kinase ◽  
Mechanistic Target Of Rapamycin ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Inhibition Of Glycolysis ◽  
Ribosomal S6 Kinase

Cells adjust to nutrient fluctuations to restore metabolic homeostasis. The mechanistic target of rapamycin (mTOR) complex 2 responds to nutrient levels and growth signals to phosphorylate protein kinases belonging to the AGC (Protein Kinases A,G,C) family such as Akt and PKC. Phosphorylation of these AGC kinases at their conserved hydrophobic motif (HM) site by mTORC2 enhances their activation and mediates the functions of mTORC2 in cell growth and metabolism. Another AGC kinase family member that is known to undergo increased phosphorylation at the homologous HM site (Ser380) is the p90 ribosomal S6 kinase (RSK). Phosphorylation at Ser380 is facilitated by the activation of the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) in response to growth factor stimulation. Here, we demonstrate that optimal phosphorylation of RSK at this site requires an intact mTORC2. We also found that RSK is robustly phosphorylated at Ser380 upon nutrient withdrawal or inhibition of glycolysis, conditions that increase mTORC2 activation. However, pharmacological inhibition of mTOR did not abolish RSK phosphorylation at Ser380, indicating that mTOR catalytic activity is not required for this phosphorylation. Since RSK and SIN1β colocalize at the membrane during serum restimulation and acute glutamine withdrawal, mTORC2 could act as a scaffold to enhance RSK HM site phosphorylation. Among the known RSK substrates, the CCTβ subunit of the chaperonin containing TCP-1 (CCT) complex had defective phosphorylation in the absence of mTORC2. Our findings indicate that the mTORC2-mediated phosphorylation of the RSK HM site could confer RSK substrate specificity and reveal that RSK responds to nutrient fluctuations.

scholarly journals Activation of the extracellular signal-regulated kinase by complement C5b-9

2005 ◽  
Vol 289 (3) ◽  
pp. F593-F603 ◽  
Author(s):  
Andrey V. Cybulsky ◽  
Tomoko Takano ◽  
Joan Papillon ◽  
Krikor Bijian ◽  
Julie Guillemette
Keyword(s):  
Protein Kinase ◽  
Actin Cytoskeleton ◽  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Glomerular Epithelial Cell ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Constitutively Active

Extracellular signals may be transmitted to nuclear or cytoplasmic effectors via the mitogen-activated protein kinases. In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury, proteinuria, and activation of phospholipases and protein kinases. This study addresses the complement-mediated activation of the extracellular signal-regulated kinase (ERK). C5b-9 induced ERK threonine202/tyrosine204 phosphorylation (which correlates with activation) in GEC in culture and PHN in vivo. Expression of a dominant-inhibitory mutant of Ras reduced complement-mediated activation of ERK, but activation was not affected significantly by downregulation of protein kinase C. Complement-induced ERK activation resulted in phosphorylation of cytosolic phospholipase A2 and was, in part, responsible for phosphorylation of mitogen-activated protein kinase-associated protein kinase-2, but did not induce phosphorylation of the transcription factor, Elk-1. Activation of ERK was attenuated by drugs that disassemble the actin cytoskeleton (cytochalasin D, latrunculin B), and these compounds interfered with the activation of ERK by mitogen-activated protein kinase kinase (MEK). Overexpression of a constitutively active RhoA as well as inhibition of Rho-associated kinase blocked complement-mediated ERK activation. Complement cytotoxicity was enhanced after disassembly of the actin cytoskeleton but was unaffected after inhibition of complement-induced ERK activation. However, complement cytotoxicity was enhanced in GEC that stably express constitutively active MEK. Thus complement-induced ERK activation depends on cytoskeletal remodelling and affects the regulation of distinct downstream substrates, while chronic, constitutive ERK activation exacerbates complement-mediated GEC injury.

ERK5 and its role in tumour development

2012 ◽  
Vol 40 (1) ◽  
pp. 251-256 ◽  
Author(s):  
Pamela A. Lochhead ◽  
Rebecca Gilley ◽  
Simon J. Cook
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Invasion And Migration ◽  
Extracellular Signal Regulated Kinase ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Tumour Cell Invasion ◽  
And Migration

The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the ‘hallmarks of cancer’ as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer.

MEK5/ERK5: Mitogen-Activated Protein Kinase 5/Extracellular Signal-Regulated Kinase 5

2012 ◽  
pp. 1074-1074
Author(s):  
Andreas Gewies ◽  
Jürgen Ruland ◽  
Alexey Kotlyarov ◽  
Matthias Gaestel ◽  
Shiri Procaccia ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein
Sign in / Sign up

Export Citation Format

Share Document