MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ

Burgermeister, Elke; Seger, Rony

doi:10.4161/cc.6.13.4453

Cited by 130 publications

(98 citation statements)

References 111 publications

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“…However, the combination of ADM, ET-743, and PPARγ in these sarcoma precursors was able to induce both CEBPα and PPARγ ( Figure 4A). Notably, PPARγ showed a mixed cytoplasmic/nuclear pattern, characteristic of an activated PPARγ pathway (29). Taken together, these data suggest that RSG is able to induce PPARγ expression only in the presence of ET-743-induced CEBPα.…”

Section: Figuresupporting

confidence: 53%

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Charytonowicz

Terry²,

Coakley³

et al. 2012

J. Clin. Invest.

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Section: Figuresupporting

confidence: 53%

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Charytonowicz

Terry²,

Coakley³

et al. 2012

J. Clin. Invest.

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“…Indeed, PPAR␥ transactivation function is attenuated by the MEK/ERK signaling cascade, either by an inhibitory phosphorylation or by modulating PPAR␥'s nucleocytoplasmic compartmentalization (13). Current experiments are in progress to identify other transcriptional pathways activated early during intestinal differentiation that could be targeted by the MEK/ERK signaling.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of the MEK/ERK pathway inhibits intestinal epithelial cell differentiation

Lemieux

Boucher

Mongrain

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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The Ras/Raf/MEK/ERK cascade regulates intestinal epithelial cell proliferation. Indeed, while barely detectable in differentiated cells of the villi, ERK1/2-activated forms are detected in the nucleus of undifferentiated human intestinal crypt cells. In addition, we and others have reported that ERKs are selectively inactivated during enterocyte differentiation. However, whether inactivation of the ERK pathway is necessary for inhibition of both proliferation and induction of differentiation of intestinal epithelial cells is unknown. Human Caco-2/15 cells, undifferentiated crypt IEC-6 cells, and differentiating Cdx3-expressing IEC-6 cells were infected with retroviruses encoding either a hemagglutinin (HA)-tagged MEK1 wild type (wtMEK) or a constitutively active S218D/S222D MEK1 mutant (caMEK). Protein and gene expression was assessed by Western blotting, semiquantitative RT-PCR, and real-time PCR. Morphology was analyzed by transmission electron microscopy. We found that 1) IEC-6/Cdx3 cells formed multicellular layers after confluence and differentiated after 30 days in culture, as assessed by increased polarization, microvilli formation, expression of differentiation markers, and ERK1/2 inhibition; 2) while activated MEK prevented neither the inhibition of ERK1/2 activities nor the differentiation process in postconfluent Caco-2/15 cells, caMEK expression prevented ERK inhibition in postconfluent IEC-6/Cdx3 cells, thus leading to maintenance of elevated ERK1/2 activities; 3) caMEK-expressing IEC-6/Cdx3 cells exhibited altered multicellular structure organization, poorly defined tight junctions, reduced number of microvilli on the apical surface, and decreased expression of the hepatocyte nuclear factor 1α transcription factor and differentiation markers, namely apolipoprotein A-4, fatty acid-binding protein, calbindin-3, mucin 2, alkaline phosphatase, and sucrase-isomaltase; and 4) increased Cdx3 phosphorylation on serine-60 (S60) in IEC-6/Cdx3 cells expressing caMEK led to decreased Cdx2 transactivation potential. These results indicate that inactivation of the ERK pathway is required to ensure the full Cdx2/3 transcriptional activity necessary for intestinal epithelial cell terminal differentiation.

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“…A key regulator of PPAR␥ activity is ERK, which has been shown to negatively regulate PPAR␥-mediated transcriptional functions either by inhibiting PPAR␥ phosphorylation or by preventing its nuclear translocation (6). ERK has been shown to negatively regulate Cav-1 expression, although its effects are species specific, as it downregulates Cav-1 levels and phosphorylation in rodent (21, 54) but not in human (54) cells.…”

Section: Discussionmentioning

confidence: 99%

Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression

Chen¹,

Whiting²,

Borza³

et al. 2010

Molecular and Cellular Biology

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Integrin ␣1␤1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin ␣1␤1-mediated EGFR activation. Integrin ␣1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin ␣1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin ␣1-null MCs decreases EGFR-mediated ROS production. We further show that integrin ␣1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor ␥ (PPAR␥), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPAR␥ or inhibition of ERK increases Cav-1 levels in the integrin ␣1-null MCs. Finally, we show that glomeruli of integrin ␣1-null mice have reduced levels of Cav-1 and activated PPAR␥ but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin ␣1␤1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPAR␥ axis plays a key role in regulating integrin ␣1␤1-dependent Cav-1 expression and consequent EGFR-mediated ROS production.Integrins are transmembrane receptors for extracellular matrix components and are composed of noncovalently bound ␣ and ␤ subunits. In mammals, 1 of 18 ␣ subunits heterodimerizes with 1 of 8 ␤ subunits to form 24 distinct integrins, each with specific but overlapping functions (4, 29). Integrins regulate cellular processes such as cell adhesion, differentiation (2), cell cycle progression (26), reactive oxygen species (ROS) production (10, 72), and extracellular matrix synthesis and remodeling (23). In addition, integrins interact with and regulate the activity of different growth factor receptors (3), and this cross talk coordinates biological processes by regulating downstream signaling pathways (8,55,58,61). Integrin occupancy causes growth factor receptor autophosphorylation (44), and growth factor receptors and integrins associate following growth factor stimulation or integrin activation (5, 61, 73).Caveolin-1 (Cav-1) is one of the three members of the caveolin family and is a structural protein involved in the formation of caveola-rich membrane domains (64). Caveolae are clearly defined, small, flask-shaped invaginations of the plasma membrane enriched in sphingolipids and cholesterol and are implicated in transcytosis, lipid metabolism, and receptor trafficking (35). Changes in plasma membrane localization and/or expression of Cav-1 can profoundly affect Cav-1-mediated functions. Different factors can regulate Cav-1 expression at both tr...

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MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ

Cited by 130 publications

References 111 publications

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

Constitutive activation of the MEK/ERK pathway inhibits intestinal epithelial cell differentiation

Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression

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