Insulin-Responsive Transcription Factors

The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues.

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Growth Promotion or Osmotic Stress Response: How SNF1-Related Protein Kinase 2 (SnRK2) Kinases Are Activated and Manage Intracellular Signaling in Plants

Plants ◽

10.3390/plants10071443 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1443

Author(s):

Yoshiaki Kamiyama ◽

Sotaro Katagiri ◽

Taishi Umezawa

Keyword(s):

Protein Kinase ◽

Plant Growth ◽

Osmotic Stress ◽

Protein Function ◽

Intracellular Signaling ◽

Growth Promotion ◽

Research Field ◽

Dependent Manner ◽

Related Protein ◽

Wide Range

Reversible phosphorylation is a major mechanism for regulating protein function and controls a wide range of cellular functions including responses to external stimuli. The plant-specific SNF1-related protein kinase 2s (SnRK2s) function as central regulators of plant growth and development, as well as tolerance to multiple abiotic stresses. Although the activity of SnRK2s is tightly regulated in a phytohormone abscisic acid (ABA)-dependent manner, recent investigations have revealed that SnRK2s can be activated by group B Raf-like protein kinases independently of ABA. Furthermore, evidence is accumulating that SnRK2s modulate plant growth through regulation of target of rapamycin (TOR) signaling. Here, we summarize recent advances in knowledge of how SnRK2s mediate plant growth and osmotic stress signaling and discuss future challenges in this research field.

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Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription

Cells ◽

10.3390/cells10040875 ◽

2021 ◽

Vol 10 (4) ◽

pp. 875

Author(s):

Gerald Thiel ◽

Tobias Schmidt ◽

Oliver G. Rössler

Keyword(s):

Transcription Factors ◽

Protein Kinase ◽

Protein Kinases ◽

Gene Transcription ◽

Intracellular Signaling ◽

Second Messengers ◽

Major Function ◽

Surface Receptors ◽

Dependent Protein

Ca2+ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca2+ concentration upon stimulation. The elevated Ca2+ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca2+ at different locations in the cell. Ca2+ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca2+ ions. A major function of the rise in intracellular Ca2+ is the change of the genetic expression pattern of the cell via the activation of Ca2+-responsive transcription factors. It has been proposed that Ca2+-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca2+. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca2+ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca2+ induces an intracellular signaling cascade, involving the activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca2+/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca2+ concentration in the cytoplasm and the nucleus, the role of Ca2+ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca2+ signaling and gene expression.

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BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling

Journal of Neurophysiology ◽

10.1152/jn.00554.2013 ◽

2014 ◽

Vol 111 (5) ◽

pp. 1008-1015 ◽

Cited By ~ 22

Author(s):

Liangfang Zhao ◽

Eric S. Levine

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Metabotropic Glutamate Receptor ◽

Glutamate Release ◽

Brain Slices ◽

Receptor Activation ◽

Inhibitory Synapses ◽

Trkb Receptor ◽

Layer 2

Endogenous cannabinoids (endocannabinoids) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent synaptic modulators that are expressed throughout the forebrain and play critical roles in many behavioral processes. Although the effects of BDNF at excitatory synapses have been well characterized, the mechanisms of action of BDNF at inhibitory synapses are not well understood. Previously we have found that BDNF suppresses presynaptic GABA release in layer 2/3 of the neocortex via postsynaptic tropomyosin-related kinase receptor B (trkB) receptor-induced release of endocannabinoids. To examine the intracellular signaling pathways that underlie this effect, we used pharmacological approaches and whole cell patch-clamp techniques in layer 2/3 pyramidal neurons of somatosensory cortex in brain slices from juvenile Swiss CD1 mice. Our results indicated that phospholipase Cγ (PLCγ) is involved in the CB1 receptor-mediated synaptic effect of BDNF, because the BDNF effect was blocked in the presence of the broad-spectrum PLC inhibitors U-73122 and edelfosine, whereas the inactive analog U-73343 did not alter the suppressive effect of BDNF at inhibitory synapses. Endocannabinoid release can also be triggered by metabotropic glutamate receptor (mGluR)-mediated activation of PLCβ, and BDNF has been shown to enhance spontaneous glutamate release. An mGluR antagonist, E4CPG, however, did not block the BDNF effect. In addition, the effect of BDNF was independent of other signaling pathways downstream of trkB receptor activation, namely, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as protein kinase C signaling.

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Deciphering the Contribution of Human Meningothelial Cells to the Inflammatory and Antimicrobial Response at the Meninges

Infection and Immunity ◽

10.1128/iai.00477-13 ◽

2013 ◽

Vol 81 (11) ◽

pp. 4299-4310 ◽

Cited By ~ 9

Author(s):

Pierre-Joseph Royer ◽

Andrew J. Rogers ◽

Karl G. Wooldridge ◽

Patrick Tighe ◽

Jafar Mahdavi ◽

...

Keyword(s):

Protein Kinase ◽

Intracellular Signaling ◽

Cell Activation ◽

Mitogen Activated Protein Kinase ◽

Meningococcal Infection ◽

Minor Role ◽

Content Type ◽

Wide Range ◽

Mitogen Activated Protein ◽

High Level

ABSTRACTWe have investigated the response of primary human meningothelial cells toNeisseria meningitidis. Through a transcriptome analysis, we provide a comprehensive examination of the response of meningothelial cells to bacterial infection. A wide range of chemokines are elicited which act to attract and activate the main players of innate and adaptive immunity. We showed that meningothelial cells expressed a high level of Toll-like receptor 4 (TLR4), and, using a gene silencing strategy, we demonstrated the contribution of this pathogen recognition receptor in meningothelial cell activation. Secretion of interleukin-6 (IL-6), CXCL10, and CCL5 was almost exclusively TLR4 dependent and relied on MyD88 and TRIF adaptor cooperation. In contrast, IL-8 induction was independent of the presence of TLR4, MyD88, and TRIF. Transcription factors NF-κB p65, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal protein kinase (JNK1), IRF3, and IRF7 were activated after contact with bacteria. Interestingly, the protein kinase IRAK4 was found to play a minor role in the meningothelial cell response toNeisseriainfection. Our work highlights the role of meningothelial cells in the development of an immune response and inflammation in the central nervous system (CNS) in response to meningococcal infection. It also sheds light on the complexity of intracellular signaling after TLR triggering.

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Genetic and Functional Investigation of Zn 2 Cys 6 Transcription Factors RSE2 and RSE3 in Podospora anserina

Eukaryotic Cell ◽

10.1128/ec.00172-13 ◽

2013 ◽

Vol 13 (1) ◽

pp. 53-65 ◽

Cited By ~ 10

Author(s):

Elodie Bovier ◽

Carole H. Sellem ◽

Adeline Humbert ◽

Annie Sainsard-Chanet

Keyword(s):

Transcription Factors ◽

Phosphoenolpyruvate Carboxykinase ◽

Constitutive Expression ◽

Podospora Anserina ◽

Loss Of Function ◽

Gene Encoding ◽

Content Type ◽

Zinc Cluster ◽

Wide Range ◽

Genes Encoding

ABSTRACT In Podospora anserina , the two zinc cluster proteins RSE2 and RSE3 are essential for the expression of the gene encoding the alternative oxidase ( aox ) when the mitochondrial electron transport chain is impaired. In parallel, they activated the expression of gluconeogenic genes encoding phosphoenolpyruvate carboxykinase ( pck ) and fructose-1,6-biphosphatase ( fbp ). Orthologues of these transcription factors are present in a wide range of filamentous fungi, and no other role than the regulation of these three genes has been evidenced so far. In order to better understand the function and the organization of RSE2 and RSE3, we conducted a saturated genetic screen based on the constitutive expression of the aox gene. We identified 10 independent mutations in 9 positions in rse2 and 11 mutations in 5 positions in rse3 . Deletions were generated at some of these positions and the effects analyzed. This analysis suggests the presence of central regulatory domains and a C-terminal activation domain in both proteins. Microarray analysis revealed 598 genes that were differentially expressed in the strains containing gain- or loss-of-function mutations in rse2 or rse3 . It showed that in addition to aox , fbp , and pck , RSE2 and RSE3 regulate the expression of genes encoding the alternative NADH dehydrogenase, a Zn 2 Cys 6 transcription factor, a flavohemoglobin, and various hydrolases. As a complement to expression data, a metabolome profiling approach revealed that both an rse2 gain-of-function mutation and growth on antimycin result in similar metabolic alterations in amino acids, fatty acids, and α-ketoglutarate pools.

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Protein kinase C-mediated phosphorylation of RKIP regulates inhibition of Na-alanine cotransport by leukotriene D4in intestinal epithelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00284.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. C1010-C1016 ◽

Cited By ~ 4

Author(s):

Subha Arthur ◽

Uma Sundaram

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Epithelial Cells ◽

Intracellular Signaling ◽

Kinase Inhibitor ◽

Intestinal Epithelial Cells ◽

Receptor Activation ◽

Intestinal Epithelial ◽

Kinase C ◽

Pka Pathway

Leukotriene D4(LTD4) is an important immune inflammatory mediator that is known to be elevated in the mucosa of chronically inflamed intestine and alter nutrient absorption. LTD4inhibits Na-alanine cotransport in intestinal epithelial cells by decreasing the affinity of the cotransporter ASCT1. LTD4is known to increase intracellular Ca++and cAMP concentrations. However, the intracellular signaling mechanism of LTD4-mediated ASCT1 inhibition is unknown. In the present study, pretreatment with calcium chelator BAPTA-AM or inhibition of Ca++-dependent protein kinase C (PKC), specifically PKCα, resulted in the reversal of LTD4-mediated inhibition of ASCT1, revealing the involvement of the Ca++-activated PKC pathway. PKCα is known to phosphorylate Raf kinase inhibitor protein (RKIP), thus activating its downstream signaling pathway. Immunoblotting with anti-RKIP-Ser153antibody showed an increase in phosphorylation levels of RKIP in LTD4-treated cells. Downregulation of endogenous RKIP showed no decrease in ASCT1 activity by LTD4, thus confirming its involvement in ASCT1 regulation. Phosphorylation of RKIP by PKC is known to activate different signaling pathways, and in this study it was found to activate cAMP-activated protein kinase A (PKA) pathway. Although protein abundance of ASCT1 was not altered in any of the experimental conditions, there was an increase in the levels of phosphothreonine in ASCT1 protein, thus showing that phosphorylation changes were responsible for the altered affinity of ASCT1 by LTD4. In conclusion, LTD4 inhibits ASCT1 through PKC-mediated phosphorylation of RKIP, leading to the subsequent activation of PKA pathway, possibly through β2-andrenergic receptor activation.

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Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling

Journal of Neurophysiology ◽

10.1152/jn.00317.2006 ◽

2007 ◽

Vol 97 (3) ◽

pp. 2448-2464 ◽

Cited By ~ 45

Author(s):

Long Chen ◽

Joseph D. Bohanick ◽

Makoto Nishihara ◽

Jeremy K. Seamans ◽

Charles R. Yang

Keyword(s):

Protein Kinase ◽

Cortical Neurons ◽

Intracellular Signaling ◽

Long Term Potentiation ◽

Receptor Activation ◽

Intrinsic Excitability ◽

Term Potentiation ◽

Voltage Dependent ◽

Spike Firing

Prefrontal cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity that may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct postsynaptic D1/5 receptor activation also modulates voltage-dependent ionic currents that regulate spike firing, thus altering the neuronal input–output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE). Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors ( Vhold = −65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2–50 μM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist SCH23390 (1 μM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297 -induced LTP-IE was significantly attenuated by Cd2+, [Ca2+]i chelation, by inhibition of phospholipase C, protein kinase-C, and Ca2+/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca2+ channels. Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca2+ influx via non-L-type Ca2+ channels, activation of PLC, intracellular Ca2+ elevation, activation of Ca2+-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s). This D1/5 receptor-mediated modulation by PKC coexists with the previously described PKA-dependent modulation of K+ and Ca2+ currents to dynamically regulate overall excitability of PFC neurons.

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Different roles for the stress-activated protein kinase pathway in the regulation of trehalose metabolism in Schizosaccharomyces pombe

Microbiology ◽

10.1099/mic.0.26279-0 ◽

2003 ◽

Vol 149 (7) ◽

pp. 1745-1752 ◽

Cited By ~ 11

Author(s):

V. Paredes ◽

A. Franco ◽

T. Soto ◽

J. Vicente-Soler ◽

M. Gacto ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factors ◽

Protein Kinase ◽

Osmotic Stress ◽

Schizosaccharomyces Pombe ◽

Fission Yeast ◽

Stress Responses ◽

Mitogen Activated Protein Kinase ◽

Wide Range ◽

Trehalose Metabolism

The Wis1p-Sty1p mitogen-activated protein kinase cascade is a major signalling system in the fission yeast Schizosaccharomyces pombe for a wide range of stress responses. It is known that trehalose functions as a protective metabolite to counteract deleterious effects of environmental stresses. Herein it is reported that the expression of genes related to trehalose metabolism in S. pombe, ntp1 + (neutral trehalase) and tps1 + [trehalose-6-phosphate (T6P) synthase], is partially regulated by the Sty1p kinase under salt-induced osmotic stress and conditions of slight oxidative stress and is fully dependent on this kinase under severe oxidative stress. This control is carried out through transcription factors Atf1p/Pcr1p during osmotic stress and through Pap1p during exposure to low levels of oxidative stress. However, all three transcription factors are needed for gene expression under conditions of extreme oxidative stress. In addition, a role for Sty1p in the modulation of post-transcriptional activation of trehalase mediated by Pka1p/Sck1p kinases, as well as in the activity of T6P synthase under such stressful conditions has been demonstrated. These results reveal a novel dual action of the Wis1p-Sty1p pathway in the regulation of trehalose metabolism in fission yeast.

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Preconditioning cultured human pediatric myocytes requires adenosine and protein kinase C

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1220 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1220-H1230 ◽

Cited By ~ 10

Author(s):

J. S. Ikonomidis ◽

T. Shirai ◽

R. D. Weisel ◽

B. Derylo ◽

V. Rao ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Phorbol Ester ◽

Adenosine Receptor ◽

Receptor Activation ◽

Receptor Stimulation ◽

Kinase C ◽

Low Volume ◽

Adenosine Receptor Activation ◽

Phosphorylation Rate

We showed previously that 20 min of low-volume anoxia ("ischemia") and 20 min of "reperfusion" preconditions quiescent pediatric myocyte cultures against damage resulting from 90 min of subsequent prolonged ischemia and 30 min of reperfusion. The purpose of this study was to assess the roles of adenosine and protein kinase C (PKC) in this preconditioning model. Our results suggest that 1) preconditioned myocytes secrete a protective mediator(s) into the "ischemic" supernatant that is transferable to other cells, and adenosine is released into the supernatant in quantities sufficient for adenosine-receptor activation (2) preconditioning is inhibited by adenosine-receptor antagonism, and myocyte protection similar to preconditioning can be achieved with exogenously administered adenosine or adenosine-receptor stimulation; (3) brief ischemic and adenosine-induced myocyte preconditioning is mimicked by the phorbol ester 4beta-phorbol 12-myristate 13-acetate (PKC agonist) and inhibited by PKC antagonists; and (4) brief ischemic and adenosine-induced myocyte preconditioning both induce PKC translocation to myocyte membranes and increase the PKC phosphorylation rate. These data suggest that adenosine released from ischemic human pediatric myocytes mediates preconditioning through activation of PKC.

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Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

Molecular and Cellular Biology ◽

10.1128/mcb.25.22.9829-9844.2005 ◽

2005 ◽

Vol 25 (22) ◽

pp. 9829-9844 ◽

Cited By ~ 52

Author(s):

Jun Wang ◽

Pierre Paradis ◽

Anne Aries ◽

Hiba Komati ◽

Chantal Lefebvre ◽

...

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Binding Sites ◽

Intracellular Signaling ◽

Receptor Activation ◽

Cardiomyocyte Hypertrophy ◽

Transcriptional Responses ◽

Stat Proteins ◽

Kinase C

ABSTRACT Angiotensin II (AII), a potent vasoactive hormone, acts on numerous organs via G-protein-coupled receptors and elicits cell-specific responses. At the level of the heart, AII stimulation alters gene transcription and leads to cardiomyocyte hypertrophy. Numerous intracellular signaling pathways are activated in this process; however, which of these directly link receptor activation to transcriptional regulation remains undefined. We used the atrial natriuretic factor (ANF) gene (NPPA) as a marker to elucidate the signaling cascades involved in AII transcriptional responses. We show that ANF transcription is activated directly by the AII type 1 receptor and precedes the development of myocyte hypertrophy. This response maps to STAT and GATA binding sites, and the two elements transcriptionally cooperate to mediate signaling through the JAK-STAT and protein kinase C (PKC)-GATA-4 pathways. PKC phosphorylation enhances GATA-4 DNA binding activity, and STAT-1 functionally and physically interacts with GATA-4 to synergistically activate AII and other growth factor-inducible promoters. Moreover, GATA factors are able to recruit STAT proteins to target promoters via GATA binding sites, which are sufficient to support synergy. Thus, STAT proteins can act as growth factor-inducible coactivators of tissue-specific transcription factors. Interactions between STAT and GATA proteins may provide a general paradigm for understanding cell specificity of cytokine and growth factor signaling.

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