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PubMed1992

Coexistence of contractile and relaxant 5-hydroxytryptamine receptors coupled to distinct signaling pathways in intestinal muscle cells: convergence of the pathways on Ca2+ mobilization.

Muscle cells were dispersed separately from circular and longitudinal muscle layers of guinea pig intestine, and 5-hydroxytryptamine (5-HT) receptors were characterized in naive cells and in cells in which one receptor type was preserved by selective receptor protection. In naive cells from both regions, 5-HT caused contraction and stimulated increases in cytosolic free calcium concentration ([Ca2+]i) (3-fold; p < 0.01) and cAMP levels (40-60%; p < 0.01) that were inhibited, respectively, by the 5-HT2 antagonist ketanserin and the 5-HT1p antagonist N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP). In circular muscle cells, where agonist-induced increase in [Ca2+]i is mediated by Ca2+ release from inositol (1,4,5)trisphosphate-sensitive stores, 5-HT caused an increase in inositol (1,4,5)trisphosphate levels that was inhibited by ketanserin. In cells maximally contracted with a non-5-HT agonist (cholecystokinin octapeptide), 5-HT caused relaxation when the contractile effect mediated by 5-HT2 receptors was blocked with ketanserin; relaxation and the concomitant increase in cAMP were inhibited by 5-HTP-DP. The singular contributions of the Ca2+ and cAMP signaling pathways were identified in cells where only one receptor type was preserved. In cells with only 5-HT2 receptors, 5-HT caused contraction and an increase in [Ca2+]i but not in cAMP levels; contraction and the increase in [Ca2+]i were inhibited by ketanserin. Conversely, in cells with only 5-HT1p receptors, 5-HT caused relaxation and an increase in cAMP levels but not in [Ca2+]i; relaxation and the increase in cAMP levels were inhibited by 5-HTP-DP. The two signaling pathways were functionally linked, converging to regulate the level of [Ca2+]i. Thus, the increase in [Ca2+]i was augmented 1) when cAMP production was inhibited by 5-HTP-DP in naive cells or 2) when cAMP production was suppressed in cells where 5-HT1p receptors were inactivated and only 5-HT2 receptors were preserved. The results imply that the increase in cAMP levels mediated by 5-HT1p receptors acted to attenuate the increase in [Ca2+]i mediated by 5-HT2 receptors. We conclude that the response to 5-HT in muscle cells is a compound effect involving activation of two receptor types coupled to distinct signaling pathways that converge on [Ca2+]i as the determinant of mechanical activity.

5-Hydroxytryptophan↗
PubMed1996

Genetic interactions indicate a role for Mdg1p and the SH3 domain protein Bem1p in linking the G-protein mediated yeast pheromone signalling pathway to regulators of cell polarity.

The pheromone signal in the yeast Saccharomyces cerevisiae is transmitted by the beta and gamma subunits of the mating response G-protein. The STE20 gene, encoding a protein kinase required for pheromone signal transduction, has recently been identified in a genetic screen for high-gene-dosage suppressors of a partly defective G beta mutation. The same genetic screen identified BEM1, which encodes an SH3 domain protein required for polarized morphogenesis in response to pheromone, and a novel gene, designated MDG1 (multicopy suppressor of defective G-protein). The MDG1 gene was independently isolated in a search for multicopy suppressors of a bem1 mutation. The MDG1 gene encodes a predicted hydrophilic protein of 364 amino acids with a molecular weight of 41 kDa that has no homology with known proteins. A fusion of Mdg1p with the green fluorescent protein from Aequorea victoria localizes to the plasma membrane, suggesting that Mdg1p is an extrinsically bound membrane protein. Deletion of MDG1 causes sterility in cells in which the wild-type G beta has been replaced by partly defective G beta derivatives but does not cause any other obvious phenotypes. The mating defect of cells deleted for STE20 is partially suppressed by multiple copies of BEM1 and CDC42, which encodes a small GTP-binding protein that binds to Ste20p and is necessary for the development of cell polarity. Elevated levels of STE20 and BEM1 are capable of suppressing a temperature-sensitive mutation in CDC42. This complex network of genetic interactions points to a role for Bem1p and Mdg1p in G-protein mediated signal transduction and indicates a functional linkage between components of the pheromone signalling pathway and regulators of cell polarity during yeast mating.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production.

Productive T cell activation leading to cytokine secretion requires the cooperation of multiple signaling pathways coupled to the TCR and to costimulatory molecules such as CD28. Here, we utilized two pharmacophores, PD98059 and FK506, that inhibit, respectively, mitogen-activated protein (MAP) kinase kinase 1 (MEK 1) and calcineurin, to determine the relative role of the signaling pathways controlled by these enzymes in T cell activation. Although the two compounds had distinctive effects on CD69 induction, they both suppressed T cell proliferation induced by anti-CD3 mAb, in a manner reversible by exogenous IL-2, suggesting that PD98059, like FK506, affects the production of, rather than the responsiveness to growth-promoting cytokines. Accordingly, IL-2 production by T cells stimulated with anti-CD3 mAb in conjunction with PMA or with anti-CD28 mAb was inhibited by both compounds. However, these compounds differentially affected the production of other cytokines, depending on the mode of activation. PD98059 inhibited TNF-alpha, IL-3, granulocyte-macrophage (GM)-CSF, IFN-gamma, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. FK506 suppressed CD3/PMA-induced production of all cytokines examined here but to a lesser extent IL-13. FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10, TNF-alpha, and IL-6 but augmented that of GM-CSF, IL-5, IFN-gamma, and IL-13. Therefore, the biochemical targets of PD98059 and FK506 contribute differently to the production of various cytokines by T cells, which may have implications for the therapeutic manipulation of this production.

CD28 Antigens↗
PubMed1996

Integrin alphavbeta3 mediates chemotactic and haptotactic motility in human melanoma cells through different signaling pathways.

Distinctions between chemotaxis and haptotaxis of cells to extracellular matrix proteins have not been defined in terms of mechanisms or signaling pathways. Migration of A2058 human melanoma cells to soluble (chemotaxis) and substratum-bound (haptotaxis) vitronectin, mediated by alphav beta3, provided a system with which to address these questions. Both chemotaxis and haptotaxis were completely inhibited by treatment with RGD-containing peptides. Chemotaxis was abolished by a blocking antibody to alphavbeta3 (LM609), whereas haptotaxis was inhibited only by approximately 50%, suggesting involvement of multiple receptors and/or signaling pathways. However, blocking antibodies to alphavbeta5, also present on A2058 cells, did not inhibit. Pertussis toxin treatment of cells inhibited chemotaxis by >80%, but did not inhibit haptotaxis. Adhesion and spreading over vitronectin induced the phosphorylation of paxillin on tyrosine. In cells migrating over substratum-bound vitronectin, tyrosine phosphorylation of paxillin increased 5-fold between 45 min and 5 h. Dilutions of anti- alphavbeta3 that inhibited haptotaxis also inhibited phosphorylation of paxillin (by approximately 50%) and modestly reduced cell spreading. In contrast, soluble vitronectin (50-100 microg/ml) did not induce tyrosine phosphorylation of paxillin. The data suggest that soluble vitronectin stimulates chemotaxis predominantly through a G protein-mediated pathway that is functionally linked to alphavbeta3. Haptotaxis is analogous to directional cell spreading and requires alphavbeta3-mediated tyrosine phosphorylation of paxillin.

Amino Acid Sequence↗
PubMed1994

Identification of the functional components of the Ras signaling pathway regulating pituitary cell-specific gene expression.

Ras, a small GTP-binding protein, is required for functional receptor tyrosine kinase signaling. Ultimately, Ras alters the activity of specific nuclear transcription factors and regulates novel patterns of gene expression. Using a rat prolactin promoter construct in transient transfection experiments, we show that both oncogenic Ras and activated forms of Raf-1 kinase selectively stimulated the cellular rat prolactin promoter in GH4 rat pituitary cells. We also show that the Ras signal is completely blocked by an expression vector encoding a dominant-negative Raf kinase. Additionally, using a molecular genetic approach, we determined that inhibitory forms of p42 mitogen-activated protein kinase and an Ets-2 transcription factor interfere with both the Ras and the Raf activation of the rat prolactin promoter. These findings define a functional requirement for these signaling constituents in the activation of the prolactin gene, a cell-specific gene which marks the lactotroph pituitary cell type. Further, this analysis allowed us to order the components in the Ras signaling pathway as it impinges on regulation of prolactin gene transcription as Ras-->Raf kinase-->mitogen-activated protein kinase-->Ets. In contrast, we show that intact c-Jun expression inhibited the Ras-induced activation of the prolactin promoter, defining it as a negative regulator of this pathway, whereas c-Jun was able to enhance the Ras activation of an AP-1-driven promoter in GH4 cells. These data show that c-Jun is not the nuclear mediator of the Ras signal for the highly specialized, pituitary cell-specific prolactin cellular promoter. Thus, we have defined a model system which provides an ideal paradigm for studying Ras/Raf signaling pathways and their effects on neuroendocrine cell-specific gene regulation.

Amino Acid Sequence↗
PubMed1995

Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation.

Two interleukin-2 receptor-dependent signaling pathways have thus far been identified: the c-fos/c-jun induction pathway mediated by src family protein-tyrosine kinases and the c-myc induction pathway. Here, we provide evidence for the existence of a third, rapamycin-sensitive pathway, which results in the induction of another proto-oncogene, bcl-2. In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway. We also provide evidence that epidermal growth factor receptor signaling may act through the same pathway that involves p56lck. These studies demonstrate a novel approach to dissecting signaling pathways regulating cellular proliferation.

Animals↗
PubMed1998

Signaling pathways mediating induction of the early response genes prostaglandin G/H synthase-2 and egr-1 by serotonin via 5-HT2A receptors.

Signaling pathways responsible for serotonin (5-HT)-mediated induction of early response genes prostaglandin G/H synthase-2 (PGHS-2, cyclooxygenase-2) and egr-1 were investigated in rat mesangial cells. Gene induction by 5-HT was dependent on 5-HT2A receptors that were pertussis toxin insensitive indicating coupling to a G-protein of the Gq family. Binding of 5-HT to this receptor activates phosphatidylinositol-specific phospholipase C (PLC) and release of Ca2+ from internal stores, but this activation was not related to PGHS-2 mRNA expression. Similarly, PI-3 kinase was not involved in 5-HT signaling. Instead, inhibition of phosphatidylcholine-specific PLC interfered with PGHS-2 and egr-1 mRNA induction, suggesting this enzyme as a link between 5-HT2A receptors and protein kinase C, an essential part of 5-HT-mediated signaling. The MAP kinase pathway was identified as common signaling pathway of 5-HT or phorbol ester-induced gene expression. Increase of intracellular cAMP by forskolin or dibutyryl cAMP did not induce PGHS-2 or egr-1 mRNA expression by itself, but strongly inhibited 5-HT-mediated mRNA induction. PGHS-2 mRNA and protein induction by 5-HT was also abolished by chelation of Ca2+ ions by EGTA, suggesting involvement of Ca2+-dependent enzymes. In contrast, egr-1 mRNA expression was superinduced in the presence of EGTA. Induction of Egr-1 protein was not changed by EGTA hinting to Ca2+-sensitive posttranscriptional steps. Activation of the Gq-coupled 5-HT2A receptor thus leads to the expression of the early response genes PGHS-2 and egr-1, using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells, respectively.

Animals↗
PubMed1992

Components of signaling pathways for insulin and insulin-like growth factor-I in muscle myoblasts and myotubes.

To survey and compare the signaling pathways from the insulin and insulin-like growth factor-I (IGF-I) receptors in undifferentiated and differentiated muscle cells, we examined the phosphotyrosine (Ptyr)-containing polypeptides elicited in L6 and Sol8 myoblasts and myotubes by the combination of insulin and IGF-I. These polypeptides were detected by immunoblotting with antibodies against Ptyr. In the L6 myoblasts and myotubes and the Sol8 myoblasts, Ptyr polypeptides of approximately 240, 175, 115, 100, 41, and 37 kilodaltons (kDa) appeared in response to insulin-IGF-I. With the Sol8 myotubes, the 240-, 175-, and 37-kDa Ptyr polypeptides were detected in basal cells, and only the Ptyr content of the 175-kDa one increased in response to insulin-IGF-I. The polypeptides of 175, 41, and 37 kDa were tentatively identified as the insulin receptor substrate 1 (IRS1) and extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), respectively, by immunoblotting with antibodies specific for these proteins, and the 115- and 100-kDa polypeptides are probably the beta-subunits of the insulin and IGF-I receptors. The amounts of IRS1, ERK1, and ERK2 were roughly the same in the L6 and Sol8 myoblasts and myotubes. Thus, differentiation of the myoblasts to myotubes was not accompanied by the detectable appearance of new insulin-IGF-I-elicited Ptyr polypeptides or marked changes in the amounts of known participants in their signaling pathways.

Animals↗
PubMed1998

Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways.

We have used the response of the superior cervical ganglia (SCG) to axotomy to investigate interactions between neuropoietic cytokines and neurotrophins. Postganglionic sympathetic axotomy leads to a prolonged leukemia inhibitory factor (LIF)-dependent activation of signal transducers and activators of transcription (STAT) factors. To study regulation of LIF-dependent activation of STAT proteins and to mimic the loss of target-derived NGF resulting from postganglionic axotomy in vivo, SCG were explanted into media lacking NGF and activation of STAT proteins was assessed by electrophoretic mobility shift assay. Like postganglionic axotomy in vivo. STAT proteins were activated for up to 8 days after explantation of SCG in vitro. SCG cultured in the presence of NGF showed decreased STAT binding when compared to ganglia cultured in NGF-free media. This inhibition of STAT activation by NGF was only present in ganglia cultured for more than 5 days and was mimicked by brain-derived neurotrophic factor (BDNF). The serine kinase inhibitor H7 augmented the increase of STAT binding produced by explantation, suggesting the presence of a labile repressor of STAT activation in the SCG. These data indicated that the neuropoietic cytokine-signaling pathway interacts with neurotrophin and H7-sensitive-signaling pathways to regulate activation of STAT proteins in sympathetic neurons. Moreover, these data suggest that one of the mechanisms leading to prolonged activation of STAT proteins after postganglionic axotomy in vivo is loss of target-derived neurotrophins.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction.

We describe here a new gene acting downstream of let-60 ras in the vulval signaling pathway of Caenorhabditis elegans. The sur-2 (suppressor of ras) gene is defined by eight mutations identified in a genetic screen for suppressors of the Multivulva phenotype of let-60(n1046), an activated let-60 ras mutation. sur-2 mutations result in pleiotropic, incompletely penetrant phenotypes that include a Vulvaless phenotype in hermaphrodites, defects in development of the male tail, gonadal abnormalities, and larval lethality, indicating a role for the sur-2 gene product in multiple developmental events. Genetic epistasis analyses suggest that sur-2 is required late in the vulval signaling pathway, downstream of let-60 Ras, and is likely to act downstream of the Raf/MAP Kinase cascade. We cloned the sur-2 gene by DNA-mediated transformation and have shown that it encodes a novel protein. We also show that a sur-2::lacZ transgene is expressed in the vulval precursor cells at the time of vulval determination.

Amino Acid Sequence↗
PubMed1997

Antagonism of cell adhesion by an alpha-catenin mutant, and of the Wnt-signaling pathway by alpha-catenin in Xenopus embryos.

In Xenopus laevis development, beta-catenin plays an important role in the Wnt-signaling pathway by establishing the Nieuwkoop center, which in turn leads to specification of the dorsoventral axis. Cadherins are essential for embryonic morphogenesis since they mediate calcium-dependent cell-cell adhesion and can modulate beta-catenin signaling. alpha-catenin links beta-catenin to the actin-based cytoskeleton. To study the role of endogenous alpha-catenin in early development, we have made deletion mutants of alphaN-catenin. The binding domain of beta-catenin has been mapped to the NH2-terminal 210 amino acids of alphaN-catenin. Overexpression of mutants lacking the COOH-terminal 230 amino acids causes severe developmental defects that reflect impaired calcium-dependent blastomere adhesion. Lack of normal adhesive interactions results in a loss of the blastocoel in early embryos and ripping of the ectodermal layer during gastrulation. The phenotypes of the dominant-negative mutants can be rescued by coexpressing full-length alphaN-catenin or a mutant of beta-catenin that lacks the internal armadillo repeats. We next show that coexpression of alphaN-catenin antagonizes the dorsalizing effects of beta-catenin and Xwnt-8. This can be seen phenotypically, or by studying the effects of expression on the downstream homeobox gene Siamois. Thus, alpha-catenin is essential for proper morphogenesis of the embryo and may act as a regulator of the intracellular beta-catenin signaling pathway in vivo.

Animals↗
PubMed2025

Interleukin-6 related signaling pathways as the intersection between chronic diseases and sepsis.

Sepsis is associated with immune dysregulated and organ dysfunction due to severe infection. Clinicians aim to restore organ function, rather than prevent diseases that are prone to sepsis, resulting in high mortality and a heavy public health burden. Some chronic diseases can induce sepsis through inflammation cascade reaction and Cytokine Storm (CS). Interleukin (IL)-6, the core of CS, and its related signaling pathways have been considered as contributors to sepsis. Therefore, it is important to study the relationship between IL-6 and its related pathways in sepsis-related chronic diseases. This review generalized the mechanism of sepsis-related chronic diseases via IL-6 related pathways with the purpose to take rational management for these diseases. IL-6 related signaling pathways were sought in Kyoto Encyclopedia of Genes and Genomes (KEGG), and retrieved protein-protein interaction in the Search for Interaction Genes tool (STRING). In PubMed and Google Scholar, the studies were searched out, which correlating to IL-6 related pathways and associating with the pathological process of sepsis. Focused on the interactions of sepsis and IL-6 related pathways, some chronic diseases have been studied for association with sepsis, containing insulin resistance, Alcoholic liver disease (ALD), Alzheimer disease (AD), and atherosclerosis. This article summarized the inflammatory mechanisms of IL-6 cross-talked with other mediators of some chronic diseases in vitro, animal models, and human experiments, leading to the activation of pathways and accelerating the progression of sepsis. The clinicians should be highlight to this kind of diseases and more clinical trials are needed to provide more reliable theoretical basis for health policy formulation.

Humans↗
PubMed1997

The proto-oncogene product p120(cbl) links c-Src and phosphatidylinositol 3'-kinase to the integrin signaling pathway.

Integrin-mediated cell adhesion triggers intracellular signaling cascades, including tyrosine phosphorylation of intracellular proteins. We show in this report that p120(cbl) (Cbl), the 120-kDa c-cbl proto-oncogene product, becomes tyrosine-phosphorylated during integrin-mediated macrophage cell adhesion to extracellular matrix substrata and anti-integrin antibodies. This tyrosine phosphorylation does not occur when cells attach to polylysine, to which cells adhere in a nonspecific fashion. It also does not take place when adhesion-induced reorganization of the cytoskeleton is inhibited with cytochalasin D. In contrast to the rapid and transient tyrosine phosphorylation of Cbl by CSF-1 stimulation, tyrosine phosphorylation of Cbl by cell attachment was gradual and persistent. Tyrosine-phosphorylated Cbl was found to form complexes with the SH2 domain-containing signaling proteins Src and phosphatidylinositol 3-kinase; in vitro kinase assays demonstrated that these kinases were active in the Cbl complexes following integrin ligand binding. Furthermore, Cbl was found to translocate to the plasma membrane in response to cell adhesion to fibronectin. These observations suggest that Cbl serves as a docking protein and may transduce signals to downstream signaling pathways following integrin-mediated cell adhesion in macrophages.

Animals↗
PubMed1998

Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry.

Signaling molecules such as Activin, Sonic hedgehog, Nodal, Lefty, and Vg1 have been found to be involved in determination of left-right (L-R) asymmetry in the chick, mouse, or frog. However, a common signaling pathway has not yet been identified in vertebrates. We report that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved in determination of L-R asymmetry in both mouse and chick. Since Pitx2 appears to be downstream of lefty-1 in the mouse pathway, we examined whether mouse Lefty proteins could affect the expression of Pitx2 in the chick. Our results indicate that a common pathway from lefty-1 to Pitx2 likely exists for determination of L-R asymmetry in vertebrates.

Animals↗
PubMed1992

Multiple Ca2+ signaling pathways converge on CaM kinase in PC12 cells.

The role of multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) in mediating various Ca2+ signaling pathways was examined in PC12 cells. Conversion of the kinase to a Ca(2+)-independent form was used to monitor which neurotransmitters activate the enzyme in situ. CaM kinase responds to Ca2+ influx elicited by ligand-gated Ca2+ channels for ATP and acetylcholine. It also responds to Ca2+ mobilization of IP3-sensitive stores elicited by phospholipase C-linked receptors for ATP and acetylcholine as well as by caffeine. CaM kinase mediates the actions of many neurotransmitters and Ca2+ signaling pathways.

Acetylcholine↗
PubMed1997

Selective loss of the calcium ion signaling pathway in T cells maturing toward a T helper 2 phenotype.

In the CD4+ T cell lineage, two well-defined differentiated populations are the Th1 and Th2 cells, which stem from a common naive T helper precursor (Thp). In this study, we begin to dissect the signaling pathways selectively used by Th1 or Th2 cells as they mature from a common naive precursor in vitro. We show that the maturing Th1 cells mount a vigorous and specific Ca2+ transient upon contact with immunogenic ligand, which is enhanced over that of the naive progenitor cells. As the cells differentiate toward a Th2 phenotype, they quickly lose the ability to engage this pathway, indicating a developmental segregation of intracellular signaling utilization. Moreover, altered peptide ligand stimulation of the Th1 line stimulates a similar Ca2+ transient as native ligand stimulation of the naive precursors, consistent with a quantitative difference in intracellular signaling by these two peptides. These data provide a direct and sequential assessment of a signaling pathway utilization in peripheral T cells as they differentiate to their final functional states.

Animals↗
PubMed1998

Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production.

Interleukin (IL)-1 is a proinflammatory cytokine with pleiotropic effects in inflammation. IL-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (MAP) kinases, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, as well as transcription factor nuclear factor kappaB (NF-kappaB). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earliest events in IL-1 signaling is the rapid interaction of IL-1 receptor-associated kinases, IRAK and IRAK-2, with the receptor complex. The relative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subsequent cellular responses have not been previously determined. To evaluate the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibroblast cells were prepared and studied. Here we report that IL-1-mediated activation of JNK, p38, and NF-kappaB were all reduced in embryonic fibroblasts deficient in IRAK expression. In addition, IL-6 production in response to IL-1 was also dramatically reduced in IRAK-deficient embryonic fibroblasts and in skin fibroblasts prepared from IRAK-deficient mice. Our results demonstrate that IRAK plays an essential proximal role in coordinating multiple IL-1 signaling pathways for optimal induction of cellular responses.

Animals↗
PubMed1995

Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells.

We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.

Acetyl-CoA Carboxylase↗