scholarly journals A Novel Regulatory Mechanism of Map Kinases Activation and Nuclear Translocation Mediated by Pka and the Ptp-Sl Tyrosine Phosphatase

1999 ◽  
Vol 147 (6) ◽  
pp. 1129-1136 ◽  
Author(s):  
Carmen Blanco-Aparicio ◽  
Josema Torres ◽  
Rafael Pulido
Keyword(s):  
Map Kinases ◽  
Nuclear Translocation ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Extracellular Signal Regulated Kinase ◽  
Inactive Form ◽  
Extracellular Signal ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Dependent Protein

Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP) kinases in the cytoplasm in an inactive form by association through a kinase interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the Ser231 residue, located within the KIM. Upon phosphorylation of Ser231, PTP-SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal–regulated kinase (ERK)1/2 and p38α were impaired. Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the Cα catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38α by wild-type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

scholarly journals Rapid Turnover of Extracellular Signal-Regulated Kinase 3 by the Ubiquitin-Proteasome Pathway Defines a Novel Paradigm of Mitogen-Activated Protein Kinase Regulation during Cellular Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4542-4558 ◽  
Author(s):  
Philippe Coulombe ◽  
Geneviève Rodier ◽  
Stéphane Pelletier ◽  
Johanne Pellerin ◽  
Sylvain Meloche
Keyword(s):  
Half Life ◽  
Map Kinases ◽  
Myogenic Differentiation ◽  
C2c12 Cells ◽  
Subcellular Targeting ◽  
Extracellular Signal Regulated Kinase ◽  
Rapid Turnover ◽  
Cellular Models ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein (MAP) kinases are stable enzymes that are mainly regulated by phosphorylation and subcellular targeting. Here we report that extracellular signal-regulated kinase 3 (ERK3), unlike other MAP kinases, is an unstable protein that is constitutively degraded in proliferating cells with a half-life of 30 min. The proteolysis of ERK3 is executed by the proteasome and requires ubiquitination of the protein. Contrary to other protein kinases, the catalytic activity of ERK3 is not responsible for its short half-life. Instead, analysis of ERK1/ERK3 chimeras revealed the presence of two destabilization regions (NDR1 and -2) in the N-terminal lobe of the ERK3 kinase domain that are both necessary and sufficient to target ERK3 and heterologous proteins for proteasomal degradation. To assess the physiological relevance of the rapid turnover of ERK3, we monitored the expression of the kinase in different cellular models of differentiation. We observed that ERK3 markedly accumulates during differentiation of PC12 and C2C12 cells into the neuronal and muscle lineage, respectively. The accumulation of ERK3 during myogenic differentiation is associated with the time-dependent stabilization of the protein. Terminal skeletal muscle differentiation is accompanied by cell cycle withdrawal. Interestingly, we found that expression of stabilized forms of ERK3 causes G1 arrest in NIH 3T3 cells. We propose that ERK3 biological activity is regulated by its cellular abundance through the control of protein stability.

scholarly journals Modelling of active forms of protein kinases: p38--a case study.

1997 ◽  
Vol 44 (3) ◽  
pp. 557-564
Author(s):  
K Ginalski ◽  
B Lesyng ◽  
J Sowadski ◽  
M Wojciechowski
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
General Scheme ◽  
Active Form ◽  
Binding Mode ◽  
Extracellular Signal Regulated Kinase ◽  
Inactive Form ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

An active form of p38 protein kinase, belonging to the mitogen-activated protein kinases subfamily, has been designed based on crystallographically known structures of two other kinases, an active form of protein kinase A (PKA) and an inactive form of extracellular signal-regulated kinase 2 (ERK2). The modelling procedure is described. Its general scheme can also be applied to other kinases. The structure of the active forms of p38 and PKA is very similar in the region which binds the substrate. The ATP-binding mode is very similar in the active forms of all the three studied kinases. Models of the active forms allow for further studies on transphosphorylation processes at the molecular level, and modelling of inhibitors competitive with ATP and/or substrates.

scholarly journals Regulation of ERK phosphorylation in differentiated arterial muscle of rabbits

2001 ◽  
Vol 281 (1) ◽  
pp. H114-H123 ◽  
Author(s):  
Paul H. Ratz
Keyword(s):  
Adrenergic Receptor ◽  
Map Kinases ◽  
Mek Inhibitor ◽  
Erk Activation ◽  
Differentiated Cells ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Isolated Arteries

Extracellular signal-regulated kinases (ERK) and mitogen-activated protein (MAP) kinases participate in cell signaling, regulating cell growth. In differentiated cells, the role ERK plays is less well known. This study quantified the degree of basal and stimulated ERK phosphorylation and contraction in freshly isolated arteries. The level of basal ERK phosphorylation was identical in preloaded and slack arteries, was greater in media than in the whole artery, and was reduced by the MAP or ERK kinase (MEK) inhibitor PD-98059. Chemical denudation using 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one did not elevate basal ERK phosphorylation. PD-98059 reduced maximum phenylephrine (PE)-stimulated ERK phosphorylation but not force. Pervanadate elevated ERK phosphorylation without causing contraction. Contractions produced by PE and relaxations produced by PE washout preceded the ERK phosphorylation. K+ depolarization, muscle stretch, and angiotensin II elevated ERK phosphorylation transiently, whereas PE maintained ERK phosphorylation for 30 min. The α1A-adrenergic receptor antagonist WB-4101 reduced PE-stimulated force by 70% and abolished PE-induced ERK phosphorylation. Afterloaded and zero-load contractions produced by K+ depolarization displayed identical increases in ERK phosphorylation. These data indicate that ERK was active basally in the differentiated artery but regulated by the endothelium and that ERK phosphorylation was not load dependent. A strong correlation between PE-induced force and ERK phosphorylation supports the hypothesis that ERK activation may reflect a signal “notifying” the cell of the degree of α1-adrenergic receptor-induced contraction.

scholarly journals The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2

1993 ◽  
Vol 296 (3) ◽  
pp. 843-849 ◽  
Author(s):  
D Stokoe ◽  
B Caudwell ◽  
P T W Cohen ◽  
P Cohen
Keyword(s):  
Protein Kinase ◽  
Substrate Specificity ◽  
Map Kinase ◽  
Catalytic Domain ◽  
Phosphorylation Site ◽  
Hydrophobic Residue ◽  
Threonine Residue ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Dependent Protein

The substrate specificity of mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MAPKAP kinase-2) was investigated by using synthetic peptides related to the N-terminus of glycogen synthase. The minimum sequence required for efficient phosphorylation was found to be Xaa-Xaa-Hyd-Xaa-Arg-Xaa-Xaa-Ser-Xaa-Xaa, where Hyd is a bulky hydrophobic residue (Phe > Leu > Val >> Ala), and the peptide Lys-Lys-Phe-Asn-Arg-Thr-Leu-Ser-Val-Ala was phosphorylated with a Km of 9.3 microM and Vmax. of 10 mumol/min per mg. MAPKAP kinase-1 (a homologue of ribosomal protein S6 kinase) also requires an arginine three residues N-terminal to the serine (position n-3), but not a hydrophobic residue at position n-5. Neither MAPKAP kinase-1 nor MAPKAP kinase-2 could tolerate a proline residue at position n + 1, indicating that their specificities do not overlap with that of MAP kinase. The specificity of calmodulin-dependent protein kinase-II resembled that of MAPKAP kinase-2, except that it could tolerate replacement of the arginine by a lysine and the phosphorylation-site serine by a threonine residue. Partial cDNAs encoding MAPKAP kinase-2 were isolated from rabbit and human skeletal muscle and human teratocarcinoma libraries, and Northern-blotting experiments revealed a single 3.3 kb mRNA transcript present at similar levels in six human tissues examined. The catalytic domain was most similar (35-40% identity) to calmodulin-dependent protein kinases II and IV, phosphorylase kinase, putative serine kinase H1 and the C-terminal domain of MAPKAP kinase-1, which form one branch of the protein kinase phylogenetic tree. The sequence N-terminal to the catalytic domain is proline-rich and contains two putative SH3-binding sites. The threonine residue phosphorylated by MAP kinase lies immediately C-terminal to the catalytic domain and is followed by a nuclear localization signal, Lys-Lys-(Xaa)10-Lys-Arg-Arg-Lys-Lys, near the C-terminus.

scholarly journals Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells

2017 ◽  
Vol 37 (15) ◽  
Author(s):  
Masamichi Imajo ◽  
Kunio Kondoh ◽  
Takuya Yamamoto ◽  
Kei Nakayama ◽  
May Nakajima-Koyama ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Retinoic Acid ◽  
Map Kinases ◽  
Retinoic Acid Receptor ◽  
Cell Fates ◽  
Acid Receptor ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Antagonistic Interactions

ABSTRACT Deregulated activation of RAS/extracellular signal-regulated kinase (ERK) signaling and defects in retinoic acid receptor (RAR) signaling are both implicated in many types of cancers. However, interrelationships between these alterations in regulating cancer cell fates have not been fully elucidated. Here, we show that RAS/ERK and RAR signaling pathways antagonistically interact with each other to regulate colorectal cancer (CRC) cell fates. We show that RAR signaling activation promotes spontaneous differentiation of CRC cells, while ERK activation suppresses it. Our microarray analyses identify genes whose expression levels are upregulated by RAR signaling. Notably, one of these genes, MKP4, encoding a member of dual-specificity phosphatases for mitogen-activated protein (MAP) kinases, mediates ERK inactivation upon RAR activation, thereby promoting the differentiation of CRC cells. Moreover, our results also show that RA induction of RAR target genes is suppressed by the ERK pathway activation. This suppression results from the inhibition of RAR transcriptional activity, which is shown to be mediated through an RIP140/histone deacetylase (HDAC)-mediated mechanism. These results identify antagonistic interactions between RAS/ERK and RAR signaling in the cell fate decision of CRC cells and define their underlying molecular mechanisms.

scholarly journals Role of Gab1 in Heart, Placenta, and Skin Development and Growth Factor- and Cytokine-Induced Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Activation

2000 ◽  
Vol 20 (10) ◽  
pp. 3695-3704 ◽  
Author(s):  
Motoyuki Itoh ◽  
Yuichi Yoshida ◽  
Keigo Nishida ◽  
Masahiro Narimatsu ◽  
Masahiko Hibi ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Map Kinases ◽  
Cytokine Signaling ◽  
Kinase Activation ◽  
Skin Development ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Stimulation Of

ABSTRACT Gab1 is a member of the Gab/DOS (Daughter of Sevenless) family of adapter molecules, which contain a pleckstrin homology (PH) domain and potential binding sites for SH2 and SH3 domains. Gab1 is tyrosine phosphorylated upon stimulation of various cytokines, growth factors, and antigen receptors in cell lines and interacts with signaling molecules, such as SHP-2 and phosphatidylinositol 3-kinase, although its biological roles have not yet been established. To reveal the functions of Gab1 in vivo, we generated mice lacking Gab1 by gene targeting. Gab1-deficient embryos died in utero and displayed developmental defects in the heart, placenta, and skin, which were similar to phenotypes observed in mice lacking signals of the hepatocyte growth factor/scatter factor, platelet-derived growth factor, and epidermal growth factor pathways. Consistent with these observations, extracellular signal-regulated kinase mitogen-activated protein (ERK MAP) kinases were activated at much lower levels in cells from Gab1-deficient embryos in response to these growth factors or to stimulation of the cytokine receptor gp130. These results indicate that Gab1 is a common player in a broad range of growth factor and cytokine signaling pathways linking ERK MAP kinase activation.

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