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 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.

Suppression of nephrin expression by TNF-α via interfering with the cAMP-retinoic acid receptor pathway

2010 ◽  
Vol 298 (6) ◽  
pp. F1436-F1444 ◽  
Author(s):  
Yukinori Saito ◽  
Maro Okamura ◽  
Shotaro Nakajima ◽  
Kunihiro Hayakawa ◽  
Tao Huang ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Map Kinases ◽  
Retinoic Acid Receptor ◽  
Selective Inhibition ◽  
Nuclear Factor Κb ◽  
Suppressive Effect ◽  
Glomerular Diseases ◽  
Acid Receptor ◽  
Dihydroxyvitamin D ◽  
Tnf Α

Nephrin, a crucial component of the slit diaphragm, is downregulated in proteinuric glomerular diseases including glomerulonephritis. We previously reported that 1) expression of nephrin in cultured podocytes is reinforced by retinoic acid (RA) and 1,25-dihydroxyvitamin D3, 2) these effects are mediated by retinoic acid receptor (RAR) and vitamin D receptor (VDR), and 3) basal and inducible expression of nephrin is downregulated by TNF-α. In the present investigation, we identified that TNF-α selectively represses activity of RAR but not VDR. To elucidate mechanisms underlying this observation, we tested involvement of downstream targets for TNF-α: nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K)-Akt, and cAMP-protein kinase A (PKA). TNF-α caused activation of NF-κB, MAP kinases, and PI3K-Akt in podocytes, whereas blockade of these molecules did not affect inhibition of RAR by TNF-α. In contrast, TNF-α depressed activity of cAMP-PKA, and blockade of PKA inhibited basal and RA-induced activation of RAR. Furthermore, activity of RAR was significantly upregulated by cAMP, and the suppressive effect of TNF-α on RAR was reversed by cAMP-elevating agents. These results suggest that 1) expression of nephrin in podocytes is regulated by the cAMP-RAR pathway and 2) suppression of nephrin by TNF-α is caused, at least in part, through selective inhibition of this pathway.

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.

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 Extracellular Signal-Regulated Kinase 7 (ERK7), a Novel ERK with a C-Terminal Domain That Regulates Its Activity, Its Cellular Localization, and Cell Growth

1999 ◽  
Vol 19 (2) ◽  
pp. 1301-1312 ◽  
Author(s):  
Mark K. Abe ◽  
Wen-Liang Kuo ◽  
Marc B. Hershenson ◽  
Marsha Rich Rosner
Keyword(s):  
Map Kinase ◽  
Cellular Localization ◽  
Map Kinases ◽  
Kinase Domain ◽  
Extracellular Signal Regulated Kinase ◽  
Terminal Domain ◽  
Inhibition Of Growth ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
And Function

ABSTRACT Mitogen-activated protein (MAP) kinases play distinct roles in a variety of cellular signaling pathways and are regulated through multiple mechanisms. In this study, a novel 61-kDa member of the MAP kinase family, termed extracellular signal-regulated kinase 7 (ERK7), has been cloned and characterized. Although it has the signature TEY activation motif of ERK1 and ERK2, ERK7 is not activated by extracellular stimuli that typically activate ERK1 and ERK2 or by common activators of c-Jun N-terminal kinase (JNK) and p38 kinase. Instead, ERK7 has appreciable constitutive activity in serum-starved cells that is dependent on the presence of its C-terminal domain. Interestingly, the C-terminal tail, not the kinase domain, of ERK7 regulates its nuclear localization and inhibition of growth. Taken together, these results elucidate a novel type of MAP kinase whereby interactions via its C-terminal tail, rather than extracellular signal-mediated activation cascades, regulate its activity, localization, and function.

Sign in / Sign up

Export Citation Format

Share Document