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Dependent Signaling Pathway (dependent + signaling_pathway)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Mechanism of insulin action on glucose metabolism in ruminants

ANIMAL SCIENCE JOURNAL, Issue 6 2002
Shin-ichi SASAKI
ABSTRACT This review presents a brief overview on the mechanism of insulin action on glucose metabolism at the molecular basis in ruminants. For ruminants, an exact mechanism of insulin on glucose metabolism is still rudimentary, but it is clear that originally, if not all, the mechanism of insulin action in ruminants was the same as in other species. Like non-ruminants, the insulin-sensitive glucose transporter GLUT 4 is thought to be a key-protein in the control of glucose uptake and metabolism in ruminants, and insulin regulates glucose transport by stimulating the translocation of GLUT 4 from an intracellular membrane pool to the plasma membrane in adipocytes and muscles. Moreover, insulin-induced GLUT 4 translocation is activated through the common intracellular signaling pathway of insulin phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway rather than the mitogen activated protein kinase (MAP kinase)-dependent signaling pathway. However, GLUT 4 mRNA and protein, and insulin-induced GLUT 4 translocation on adipocytes and muscles in ruminants are lower than those in rodents and human subjects. Furthermore, insulin-induced PI3-kinase activation is reduced concomitantly with the lower content of insulin receptor substrate-1 (IRS-1) in ruminants. In spite of normal status, a resistance to the stimulatory action of insulin on glucose metabolism in ruminants as compared to non-ruminants may be due to, at least in part, the lower content of GLUT 4 and the lower capacity of insulin signal transduction, resulting to the lower glucose transport activity. [source]

Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin ,v-mediated ADAM activity in hepatocellular carcinoma: A novel functional target for gefitinib

CANCER SCIENCE, Issue 2 2006
Mitsuhiro Matsuo
We have shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (,Iressa', ZD1839) inhibits the development of intrahepatic metastases of hepatocellular carcinoma CBO140C12, and EGFR transactivation by tumor necrosis factor-, is a possible target of gefitinib. In the present study, we focused on the fibronectin (FN)-dependent signaling pathway to further elucidate the antimetastatic activity of gefitinib in CBO140C12 cells. We initially observed that FN induced activation of extracellular signal-regulated kinase (ERK), p38 and Akt, as well as cell proliferation and CBO140C12 cell invasion. These responses were mediated by EGFR tyrosine kinase, because gefitinib inhibited these effects of FN. FN-induced ERK, p38 and Akt activation was partly blocked by the Arg-Gly-Asp (RGD)-pseudo-peptide FC-336, anti-,v integrin antibody RMV-7, the broad-spectrum matrix metalloprotease inhibitor GM6001 and the broad spectrum a disintegrin and metalloprotease (ADAM) inhibitor TAPI-1. But these inhibitors had no effect on EGF-induced signaling pathways, suggesting that integrins and ADAM may be upstream components of EGFR in these responses. These results suggest that FN-induced activation of ERK, p38, Akt, cell proliferation and invasion was mediated, at least in part, via integrins, ADAM and EGFR, and that this FN-induced signaling pathway might be involved in the antimetastatic activity of gefitinib. (Cancer Sci 2006; 97: 155 ,162) [source]

Human lactoferrin activates NF-,B through the Toll-like receptor 4 pathway while it interferes with the lipopolysaccharide-stimulated TLR4 signaling

FEBS JOURNAL, Issue 9 2010
Ken Ando
Lactoferrin (LF) has been implicated in innate immunity. Here we reveal the signal transduction pathway responsible for human LF (hLF)-triggered nuclear factor-,B (NF-,B) activation. Endotoxin-depleted hLF induces NF-,B activation at physiologically relevant concentrations in the human monocytic leukemia cell line, THP-1, and in mouse embryonic fibroblasts (MEFs). In MEFs, in which both tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 are deficient, hLF causes NF-,B activation at a level comparable to that seen in wild-type MEFs, whereas TRAF6-deficient MEFs show significantly impaired NF-,B activation in response to hLF. TRAF6 is known to be indispensable in leading to NF-,B activation in myeloid differentiating factor 88 (MyD88)-dependent signaling pathways, while the role of TRAF6 in the MyD88-independent signaling pathway has not been clarified extensively. When we examined the hLF-dependent NF-,B activation in MyD88-deficient MEFs, delayed, but remarkable, NF-,B activation occurred as a result of the treatment of cells with hLF, indicating that both MyD88-dependent and MyD88-independent pathways are involved. Indeed, hLF fails to activate NF-,B in MEFs lacking Toll-like receptor 4 (TLR4), a unique TLR group member that triggers both MyD88-depependent and MyD88-independent signalings. Importantly, the carbohydrate chains from hLF are shown to be responsible for TLR4 activation. Furthermore, we show that lipopolysaccharide-induced cytokine and chemokine production is attenuated by intact hLF but not by the carbohydrate chains from hLF. Thus, we present a novel model concerning the biological function of hLF: hLF induces moderate activation of TLR4-mediated innate immunity through its carbohydrate chains; however, hLF suppresses endotoxemia by interfering with lipopolysaccharide-dependent TLR4 activation, probably through its polypeptide moiety. [source]

Glutamate receptors on myelinated spinal cord axons: II.

ANNALS OF NEUROLOGY, Issue 2 2009
GluR5 receptors
Objective Glutamate receptors, which play a major role in the physiology and pathology of central nervous system gray matter, are also involved in the pathophysiology of white matter. However, the cellular and molecular mechanisms responsible for excitotoxic damage to white matter elements are not fully understood. We explored the roles of AMPA and GluR5 kainate receptors in axonal Ca2+ deregulation. Methods Dorsal column axons were loaded with a Ca2+ indicator and imaged in vitro using confocal microscopy. Results Both AMPA and a GluR5 kainate receptor agonist increased intraaxonal Ca2+ in myelinated rat dorsal column fibers. These responses were inhibited by selective antagonists of these receptors. The GluR5-mediated Ca2+ increase was mediated by both canonical (ie, ionotropic) and noncanonical (metabotropic) signaling, dependent on a pertussis toxin,sensitive G protein/phospholipase C,dependent pathway, promoting Ca2+ release from inositol triphosphate,dependent stores. In addition, the GluR5 response was reduced by intraaxonal NO scavengers. In contrast, GluR4 AMPA receptors operated via Ca2+ -induced Ca2+ release, dependent on ryanodine receptors, and unaffected by NO scavengers. Neither pathway depended on L-type Ca2+ channels, in contrast with GluR6 kainate receptor action.1 Immunohistochemistry confirmed the presence of GluR4 and GluR5 clustered at the surface of myelinated axons; GluR5 coimmunoprecipitated with nNOS and often colocalized with neuronal nitric oxide synthase clusters on the internodal axon. Interpretation Central myelinated axons express functional AMPA and GluR5 kainate receptors, and can directly respond to glutamate receptor agonists. These glutamate receptor,dependent signaling pathways promote an increase in intraaxonal Ca2+ levels potentially contributing to axonal degeneration. Ann Neurol 2009 [source]