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PubMed2004

Activation of the hexosamine pathway leads to phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 and impairs the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin insulin biosynthetic pathway in RIN pancreatic beta-cells.

Many adverse effects of glucose were attributed to its increased routing through the hexosamine pathway (HBP). There is evidence for an autocrine role of the insulin signaling in beta-cell function. We tested the hypothesis that activation of the HBP induces defects in insulin biosynthesis by affecting the insulin-mediated protein translation signaling. Exposure of human pancreatic islets and RIN beta-cells to glucosamine resulted in reduction in glucose- and insulin-stimulated insulin biosynthesis, which in RIN beta-cells was associated with impairment in insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation at Tyr(608) and Tyr(628), which are essential for engaging phosphatidylinositol 3-kinase (PI 3-kinase). These changes were accompanied by impaired activation of PI 3-kinase, and activation of Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. RIN beta-cells exposed to high glucose exhibited increased c-Jun N-terminal kinase (JNK) and ERK1/2 activity, which was associated with increased IRS-1 phosphorylation at serine (Ser)(307) and Ser(612), respectively, that inhibits coupling of IRS-1 to the insulin receptor and is upstream of the inhibition of IRS-1 tyrosine phosphorylation. Azaserine reverted the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Glucosamine mimicked the stimulatory effects of high glucose on JNK and ERK1/2 activity and IRS-1 phosphorylation at Ser(307) and Ser(612). Inhibition of JNK and MAPK kinase-1 activity reverted the negative effects of glucosamine on insulin-mediated protein synthesis. These results suggest that activation of the HBP accounts, in part, for glucose-induced phosphorylation at Ser(307) and Ser(612) of IRS-1 mediated by JNK and ERK1/2, respectively. These changes result in impaired coupling of IRS-1 and PI 3-kinase, and activation of the Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2001

The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo.

The 40 notochord cells of the ascidian tadpole invariably arise from two different lineages: the primary (A-line) and the secondary (B-line) lineages. It has been shown that the primary notochord cells are induced by presumptive endoderm blastomeres between the 24-cell and the 64-cell stage. Signaling through the fibroblast growth factor (FGF) pathway is required for this induction. We have investigated the role of the bone morphogenetic protein (BMP) pathway in ascidian notochord formation. HrBMPb (the ascidian BMP2/4 homologue) is expressed in the anterior endoderm at the 44-cell stage before the completion of notochord induction. The BMP antagonist Hrchordin is expressed in a complementary manner in all surrounding blastomeres and appears to be a positive target of the BMP pathway. Unexpectedly, chordin overexpression reduced formation of both primary and secondary notochord. Conversely, primary notochord precursors isolated prior to induction formed notochord in presence of BMP-4 protein. While bFGF protein had a similar activity, notochord precursors showed a different time window of competence to respond to BMP-4 and bFGF. Our data are consistent with bFGF acting from the 24-cell stage, while BMP-4 acts during the 44-cell stage. However, active FGF signaling was also required for induction by BMP-4. In the secondary lineage, notochord specification also required two inducing signals: an FGF signal from anterior and posterior endoderm from the 24-cell stage and a BMP signal from anterior endoderm during the 44-cell stage.

Animals↗

PubMed1998

Stepwise activation of the gonadotropic signal transduction pathway, and the ability of prostaglandin F2alpha to inhibit this activated pathway.

Through selective activation of the gonadotropic signal transduction pathway, we have determined the probable site of the antigonadotropic effects of prostaglandin F2alpha (PGF2alpha) in the human granulosa-luteal cell (hGLC). The gonadotropic signal transduction pathway was activated at the level of the receptor (luteinizing hormone and beta-adrenergic), stimulatory G protein (Gs), adenylate cyclase (AC), and protein kinase A (PKA) by human chorionic gonadotropin (hCG) and isoproterenol (Iso), cholera toxin (CTX), forskolin, and dibutryl cAMP (Db cAMP), respectively. Concomitantly, the ability of PGF2alpha to inhibit progesterone production in response to the activation of this cascade at these different levels was examined. hGLCs were obtained from in vitro fertilization patients and were precultured for 8 d in Medium 199 supplemented with fetal bovine serum (M199; 10% FBS). Following the preculture period, cells were treated with either vehicle or one of the above activators of the gonadotropic pathway, either in the absence or presence of PGF2alpha (in M199; No FBS). Following the treatment period, media were collected and assayed for progesterone by RIA. Prostaglandin F2alpha (10(-6) M) significantly inhibited hCG (1 IU/mL), Iso (10(-5) M), CTX (1 microg/mL), and forskolin- (10(-5) M) stimulated progesterone production. Conversely, PGF2alpha did not inhibit progesterone production stimulated by a saturating concentration of Db cAMP (10(-6) M). The ability of PGF2alpha to inhibit hCG- or CTX-stimulated progesterone production was attenuated by pertussis toxin (PTX; 50 ng/mL). In conclusion, through a pertussis toxin-sensitive G protein, PGF2alpha inhibits progesterone production at a level below AC, and above the activation of PKA by cAMP.

Adenylyl Cyclases↗

PubMed1994

Optic pathway glioma infiltrating into somatostatinergic pathways in a young boy with gigantism. Case report.

The authors report gigantism in a 16-month-old boy with an extensive optic pathway glioma infiltrating into somatostatinergic pathways, as revealed by magnetic resonance imaging and immunocytochemical studies. Stereotactic biopsies of areas showing hyperintense signal abnormalities on T2-weighted images in and adjacent to the involved visual pathways provided rarely obtained histological correlation of such areas. The patient received chemotherapy, which resulted in reduction of size and signal intensity of the tumor and stabilization of vision and growth velocity.

Astrocytoma↗

PubMed2002

Regulation of Ca2+ entry pathways by both limbs of the phosphoinositide pathway.

All inositol 1,4,5-trisphosphate (InsP3) receptors are biphasically regulated by cytosolic Ca2+. For type 2 InsP3 receptors, InsP3 binding controls whether a stimulatory Ca2+-binding site (exposed after InsP3 binding) or an inhibitory Ca2+-binding site (exposed only in the absence of InsP3) is accessible. Ca2+ therefore inhibits these InsP3 receptors only after InsP3 has dissociated. The capacitative Ca2+ entry (CCE) pathway is activated by depletion of Ca2+ stores, but the local increase in cytosolic [Ca2+] as Ca2+ flows through these channels could cause long-lasting inhibition of InsP3 receptors and so termination of the signal that activates CCE. However, the duration of the openings of CCE channels is matched to the behaviour of InsP3 receptors such that during the brief openings of CCE channels, active InsP3 receptors are unlikely to lose enough InsP3 for them to become inhibited. In A7r5 vascular smooth muscle cells, CCE and a non-capacitative Ca2+ entry (NCCE) pathway, which is activated by arachidonic acid released from diacylglycerol by diacylglycerol lipase, can be distinguished by their different permeation properties and sensitivity to selective blockers. Arachidonic acid also inhibits CCE and so ensures that during receptor activation only the NCCE pathway mediates Ca2+ entry, while CCE contributes only after removal of the agonist.

Animals↗

PubMed1992

Effect of efferentiectomy on enzymes of glycolytic pathway, HMP pathway and TCA cycle in epididymis and vas deferens of rhesus monkey.

The importance of exocrine secretions of testis in the regulation of energy metabolism of the epididymis and vas deferens was examined in rhesus monkeys by performing efferentiectomy. At autopsy the epididymis was divided into initial segment, caput, corpus and cauda portions to make an account of regional differences, if any. Eleven enzymes of glycolysis, two key enzymes of HMP pathway and seven enzymes of TCA cycle were assayed in the epididymal segments and vas deferens of control (intact) and experimental (efferentiectomised for 90 days) monkeys. The results indicate that while anaerobic energy metabolism (glycolysis and HMP pathway) is sensitive to efferentiectomy chiefly in the proximal regions of epididymis, the oxidative pathway (TCA cycle) is dependent on testicular exocrine secretions throughout the length of epididymis, as well as in the vas deferens. Since all androgen-sensitive enzymes do not regress after efferentiectomy, it is suggested that unidentified exocrine factors of testis may have role in regulating energy metabolism in the epididymis and vas deferens.

Animals↗

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↗

PubMed2006

Serrated pathway and APC (conventional)-type colorectal polyps: molecular-morphologic correlations, genetic pathways, and implications for classification.

This review addresses the genetic mutations and cell signaling pathway alterations in colorectal premalignant polyps, focusing on the link between molecular changes and morphologic features. Biallelic APC (adenomatous polyposis coli) mutations are directly responsible for the specific and characteristic cytologic features of dysplastic cells in conventional tubular adenomas. Sessile serrated adenomas (SSAs) are the precursor lesions of the serrated neoplasia pathway. The BRAF activating mutation and hypermethylation of SLC5A8, which mediates short chain fatty acid transport, may be the important events in the genesis of SSAs. Intracellular butyrate inhibits histone deacetylase, allowing histone hyperacetylation and, eventually, transcriptional activation of specific genes. Decreased p21(WAF1/CIP1) and activation of the mitogen-activated protein kinase pathway may be the key intermediary alterations. Progressive loss of cell cycle control and decreased and altered cytoplasmic differentiation produce the characteristic constellation of morphologic changes of SSAs and traditional serrated adenomas.

Adaptor Proteins, Signal Transducing↗

PubMed1989

[Paroxysmal tachycardia with long QRS (left branch block type) in a female patient with accessory nodo-ventricular pathway. Role of the anomalous pathway in the electrogenesis of the arrhythmia].

The authors report a case of paroxysmal tachycardia with widened QRS (left bundle branch block morphology), where the electrophysiologic investigation shows an accessory nodo-ventricular pathway and suggests its involvement, as descendent (anterograde) pathway in a circular movement, the ascendant (retrograde) limb of which is the nodo-hisian pathway.

Adult↗

PubMed1988

Extrinsic-pathway enzyme-linked coagulation assay (EP-ELCA). A clot-based alternative to prothrombin time for measurement of extrinsic pathway factors in plasma.

This solid-phase colorimetric microtiter-plate clotting assay is much more sensitive than standard clotting tests. In enzyme-linked coagulation assay (ELCA), enzyme-labeled fibrinogen and solid-phase fibrinogen are the substrate for thrombin generated in the clotting cascade. We used this assay to measure the factors of the extrinsic pathway by an extrinsic pathway-specific assay (EP-ELCA) and to determine the individual factors of the extrinsic pathway (VII, X, V, II) in plasmas of coumadin-treated and heparin-treated patients, with prothrombin time (PT) values used as a reference. In the ELCA method, samples and controls are incubated on the same plate, eliminating the requirement for pre-standardization of the substrate "plasma" before the factor assay is done. Concentrations of factors are determined by serially diluting sample and control plasmas to yield equivalent activity at given dilutions, a more direct approach for measuring specific factors than determining log concentrations vs log clotting time. Changes in the concentrations of clotting factors are seen before changes are apparent by PT. For coumadin-treated patients, all vitamin K-dependent factors were significantly (P less than or equal to 0.001) less than in normal controls, whereas factor V concentrations were normal, as expected. For patients treated with heparin, concentrations of factors X and VII were less than in normal controls (P less than 0.01) and results for EP-ELCA, II, and V assays were normal. This methodology can readily be automated.

Adult↗

PubMed1975

[Tachycardia caused by reciprocal rhythm between normal pathways and a rapid atrial-His pathway].

Report of one unhabitual case of reciprocal rhythm with anterograde conduction through James' fibres and retrograde conduction through the normal nodal pathways. The reality of an anterograde nodal short-circuit is indicated by many arguments, and in particular by the presence of a double ventricular response, after induced atrial premature beats reaching the ventricle once by the rapid pathway and the second time by the slow pathway.

Bundle of His↗

PubMed1995

Burn injury stimulates multiple proteolytic pathways in skeletal muscle, including the ubiquitin-energy-dependent pathway.

BACKGROUND: Burn injury is associated with increased muscle protein breakdown. However, the role of different intracellular proteolytic pathways in burn-induced muscle proteolysis is not known. STUDY DESIGN: A 30 percent total body surface area burn injury was inflicted on rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents leupeptin and methylamine. Calcium-dependent proteolysis was determined by incubating muscles in the absence or presence of calcium or by blocking the calcium-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of adenosine triphosphate (ATP) by 2-deoxyglucose and 2,4-dinitrophenol. Muscle ubiquitin messenger RNA (mRNA) was determined by Northern blot analysis to assess ATP-ubiquitin-dependent proteolysis. RESULTS: Calcium-dependent total protein breakdown was stimulated in muscles from burned rats. However, the sensitivity to calcium in vitro was not increased after burn. The lysosomal and energy-dependent components of total protein breakdown were doubled in muscles from burned rats and the energy-dependent myofibrillar protein breakdown was increased almost seven-fold. Ubiquitin mRNA was increased in muscles from burned rats. CONCLUSIONS: Burn injury stimulates multiple proteolytic pathways in skeletal muscle. The ubiquitin-energy-dependent pathway may be particularly important for the breakdown of myofibrillar proteins.

Animals↗

PubMed1996

IL-4 protects cells from apoptosis via the insulin receptor substrate pathway and a second independent signaling pathway.

Although it has been known for some time that IL-4 protects cells from death via apoptosis, very little is known about the mechanism by which IL-4 exerts this effect. In this report, we have studied the molecular mechanisms of the IL-4-induced prevention of apoptosis in the 32D and B cell systems. IL-3 withdrawal has been shown to induce G1-arrest in 32D cells and subsequent death by apoptosis. We found that overexpression of IRS-1 protected 32D cells from death induced by IL-3 deprivation. IL-4 was able to protect 32D cells from apoptosis in the presence or absence of IRS-1. However, the protection from apoptosis of cells cultured in IL-4 was greater in the presence of IRS-1 and it reached levels comparable to those of cells cultured in IL-3. The IRS-1-dependent prevention of apoptosis is linked to the activation of PI 3'-kinase since wortmannin and LY294002, two inhibitors of PI 3'-K, partially inhibited the prevention of apoptosis mediated by IL-4 in 32D-IRS-1 cells after IL-3 withdrawal but not in 32D cells lacking IRS-1 expression. In addition, we found that the IRS/PI 3'-K pathway is, at least in part, responsible for the prevention of apoptosis by IL-4 in normal splenic B cell cultures. In spite of the ability of murine IL-4 to partially protect 32D cells lacking IRS-1 from apoptosis, human IL-4 was not able to prevent cell death in 32D-IRS-1 cells transfected with the human IL-4 receptor mutated in the insulin-lL-4 receptor motif (14R-motif) at amino acid 497 (Y497F). This mutation has previously been shown to abrogate the tyrosine phosphorylation of IRS-1 by human IL-4. These results demonstrate that IL-4 protects 32D cells from apoptosis by two different pathways, one of them mediated by IRS-1. In addition, these results suggest that the 14R-motif of the IL-4R is linked to both pathways.

Animals↗

PubMed1996

["Double nodal pathway" as a common electrogenic pathway at the base of first and second degree paroxysmal atrioventricular node and nodal reentrant tachycardia].

The combined occurrence of conduction disturbances and reentry in subjects with a dual atrioventricular nodal pathway is extremely rare and poorly documented, only by means of short electrocardiographic strips. This case report deals with a young woman with frequent episodes of paroxysmal first- and second-degree type I atrioventricular block due to a dual atrioventricular nodal pathway at Holter monitoring, and atrioventricular nodal reentrant tachycardia inducible at transesophageal electrophysiologic study. This case confirms that some paroxysmal first- and second-degree atrioventricular block and the atrioventricular nodal reentrant tachycardia may share the same electrogenetic substrate represented by a dual atrioventricular nodal pathway. This finding may be of clinical significance because of its potential therapeutical implications. Further studies are needed in order to explain the rarity of this association.

Adult↗

PubMed1995

On-pathway versus off-pathway folding intermediates.

Rapidly formed molten globule intermediates accumulate at the start of the folding reactions of several small proteins. Opinion is sharply divided as to whether they are on-pathway or off-pathway intermediates. I discuss recent experiments aimed at resolving this issue. Specific points include whether a 'rollover' in the plot of folding rate versus denaturant concentration implies that a folding intermediate is or is not on-pathway; whether the failure to observe folding intermediates for some small proteins implies a different folding mechanism or only that the intermediates are less stable; possible interpretation of 'fast-track' folding of hen lysozyme; and the significance of recent results in the search for unfolding intermediates.

Journal Article↗

PubMed1997

A novel degradation pathway of tissue factor pathway inhibitor: incorporation into fibrin clot and degradation by thrombin.

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor with three tandem inhibitory domains (K1, K2, and K3) that regulates the initial reactions of the extrinsic blood coagulation pathway through K1 and K2. In the present study, the effect of thrombin on TFPI in a purified system was first examined using recombinant TFPI from Chinese hamster ovary (CHO) cells. TFPI was inactivated by thrombin with cleavage of three peptide bonds, Lys 254-Thr 255 in the C-terminal basic region, Arg 107-Gly 108 (reactive site toward factor Xa in K2), and Lys 86-Thr 87 between K1 and K2. Then, degradation of radiolabeled TFPI by thrombin was examined in two systems: (1) mixed with plasma and then tissue factor (TF) and calcium ion, and (2) mixed with fibrinogen and then thrombin. TFPI degradation was detected in serum from normal plasma and more extensively from anti-thrombin (AT)-depleted plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Significant radioactivity was found in the clot after coagulation of the plasma, which decreased after 20 hours' incubation. These changes were more prominent in AT-depleted plasma than in normal plasma. When TFPI lacking the C-terminal basic region was used instead of full-length TFPI, most of the radioactivity was found in serum rather than in fibrin clots. Incorporation of TFPI into the fibrin clot was prevented by a synthetic C-terminal peptide of TFPI. Similar results were obtained after mixing radiolabeled TFPI with fibrinogen and then thrombin in the presence of calcium ion or EDTA. These results demonstrate a novel degradation pathway of TFPI, ie, incorporation into fibrin via the C-terminal basic region and degradation by thrombin (possibly fibrin-bound thrombin).

Animals↗

PubMed1982

A one-step procedure for preparation of classical pathway (C1q) and alternative pathway (factor D) depleted human serum.

A simple method for preparation of a serum depleted in both C1q and Factor D is described. The hemolytic activities of both pathways are completely abolished and can be fully restored using the respective purified complement components. Furthermore, this serum is useful for studying cell systems since blocking either complement pathway does not require chelating agents.

Binding, Competitive↗

PubMed2003

On the site of C4 deposition upon complement activation via the mannan-binding lectin pathway or the classical pathway.

The mannan-binding lectin (MBL) pathway and the classical pathway of complement activation are initiated by the binding of the recognition structure of the initiator complexes, MBL and C1q, respectively, to their ligands, i.e. carbohydrate structures or immune complexes. Proenzymes associated with MBL or C1q are then activated and generate C3 convertase through the activation of C4 and C2. The cleavage product of C4, C4b, attaches covalently to nearby hydroxyl or amino groups. The current picture is that C2 must then attach to C4b before being cleaved by the same associated proteases into the enzymatically active fragment, C2b. This suggests a stringent requirement for the deposition of C4b very close to the initiator complex, or indeed onto the initiator complex. We examined the possibility of C4b being bound to the initiator complex by a solid-phase assay, allowing for the selective elution of the initiator complexes, followed by quantification of the C4b being eluted and the C4b remaining on the solid phase. Also, we estimated the generation of complexes between the released initiator complex and C4b. More than 99% of deposited C4b was bound directly to the solid phase rather than to the initiator complex. Our approach cannot answer the question of the whereabouts of the C2 when it is cleaved.

Binding Sites↗