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At least 1,099 records · Page 61Linked to original sources
PubMed2002

beta 1 integrin regulates fibroblast viability during collagen matrix contraction through a phosphatidylinositol 3-kinase/Akt/protein kinase B signaling pathway.

Integrins regulate cell viability through their interaction with the extracellular matrix. Integrins can sense mechanical forces arising from the matrix and convert these stimuli to chemical signals capable of modulating intracellular signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is a major regulator of cell survival. It is not known, however, whether integrins, acting as mechanoreceptors, regulate cell survival via the PI3K/Akt pathway. Here, we show that in response to a matrix-derived mechanical stimulus, beta1 integrin regulated cell viability by regulating Akt activity in a PI3K-dependent fashion. To accomplish this, we employed fibroblasts cultured in collagen gels. During contraction of collagen matrices, fibroblasts underwent apoptosis. We demonstrate that ligation of beta1 integrin with anti-beta1 integrin antibodies protected fibroblasts from apoptosis. The nature of the survival signal activated by beta1 integrin engagement with antibody was mediated by PI3K acting through Akt/protein kinase B. We show that Akt phosphorylation decreased during collagen contraction and that this decrease correlated precisely with the onset of fibroblast apoptosis. Fibroblasts transfected with constitutively active PI3K displayed increased Akt phosphorylation and were protected from anoikis and collagen gel contraction-induced apoptosis. Our data identify a novel role for beta1 integrin in regulating fibroblast viability through a PI3K/Akt/protein kinase B signaling pathway in response to a matrix-derived mechanical stimulus.

Antibodies↗
PubMedDate not supplied

Novel signaling pathways contributing to vascular changes in hypertension.

In hypertension, increased peripheral resistance maintains elevated levels of arterial blood pressure. The increase in peripheral resistance results, in part, from abnormal constrictor and dilator responses and vascular remodeling. In this review, we consider four cellular signaling pathways as possible explanations for these abnormal vascular responses: (1) augmented signaling via the epidermal growth factor receptor to cause remodeling of the cerebrovasculature; (2) reduced sphingolipid signaling leading to blunted vasodilation and increased smooth muscle proliferation; (3) increased signaling via Rho/Rho kinase leading to enhanced vasoconstriction, and (4) a relative state of microtubular depolymerization favoring vasoconstriction in hypertension. These novel cell signaling pathways provide new pharmacological targets to reduce total peripheral vascular resistance in hypertension.

Angiotensin II↗
PubMed2003

Discrete functions of TRAF1 and TRAF2 in Drosophila melanogaster mediated by c-Jun N-terminal kinase and NF-kappaB-dependent signaling pathways.

Two Drosophila tumor necrosis factor receptor-associated factors (TRAF), DTRAF1 and DTRAF2, are proposed to have similar functions with their mammalian counterparts as a signal mediator of cell surface receptors. However, their in vivo functions and related signaling pathways are not fully understood yet. Here, we show that DTRAF1 is an in vivo regulator of c-Jun N-terminal kinase (JNK) pathway in Drosophila melanogaster. Ectopic expression of DTRAF1 in the developing eye induced apoptosis, thereby causing a rough-eye phenotype. Further genetic interaction analyses revealed that the apoptosis in the eye imaginal disc and the abnormal eye morphogenesis induced by DTRAF1 are dependent on JNK and its upstream kinases, Hep and DTAK1. In support of these results, DTRAF1-null mutant showed a remarkable reduction in JNK activity with an impaired development of imaginal discs and a defective formation of photosensory neuron arrays. In contrast, DTRAF2 was demonstrated as an upstream activator of nuclear factor-kappaB (NF-kappaB). Ectopic expression of DTRAF2 induced nuclear translocation of two Drosophila NF-kappaBs, DIF and Relish, consequently activating the transcription of the antimicrobial peptide genes diptericin, diptericin-like protein, and drosomycin. Consistently, the null mutant of DTRAF2 showed immune deficiencies in which NF-kappaB nuclear translocation and antimicrobial gene transcription against microbial infection were severely impaired. Collectively, our findings demonstrate that DTRAF1 and DTRAF2 play pivotal roles in Drosophila development and innate immunity by differentially regulating the JNK- and the NF-kappaB-dependent signaling pathway, respectively.

Animals↗
PubMed2005

Effects of NH4Cl intake on renal growth in rats: role of MAPK signalling pathway.

BACKGROUND: There is a surprising lack of experimental data on the mechanisms of NH4Cl-induced chronic metabolic acidosis which causes kidney hypertrophy. The NH4Cl treatment results in an absolute increase in kidney mass. Despite findings to indicate a close interaction between NH4Cl-induced chronic metabolic acidosis and renal enlargement, the role of the stimulated serine kinase cascade, mediated by the stepwise activation of extracellular signal-regulated kinase (ERK) signalling, on kidney hypertrophy has not yet been investigated. METHODS: To test this hypothesis, the present study was undertaken to further explore the possible involvement of mitogen-activated protein kinase (MAPK) signalling pathway in renal growth in chronic NH4Cl-treated rats by western blot analysis. RESULTS: Our major findings are as follows: (1) Urinary sodium excretion significantly increased during the early phases of NH4Cl-induced acidosis, (2) This occurrence is associated with sustained renal hypertrophy, and (3) sustained basal phosphorylation of IRS-1, Shc, and MAPK/ERKs in acidotic kidneys. CONCLUSIONS: The present study confirms that NH4Cl-induced acidosis causes disturbances in renal sodium handling. In addition, these findings demonstrate a sustained pre-stimuli activation of kidney MAPK/ERKs signalling pathways in the NH4Cl-treated rats that may correlate with an increased rate of kidney hypertrophy and a transient renal tubule inability to handle sodium. Thus, the altered renal electrolyte handling may result from a reciprocal relationship between the level of renal tubule metabolic activity and ion transport. In addition, the study shows that the appropriate regulation of tyrosine kinase protein phosphorylation, and its downstream signal transduction pathway, plays an important role on renal growth in the NH4Cl-treated rats.

Acidosis, Renal Tubular↗
PubMed1999

Distinct signaling pathways mediate touch and osmosensory responses in a polymodal sensory neuron.

The Caenorhabditis elegans ASH sensory neurons mediate responses to nose touch, hyperosmolarity, and volatile repellent chemicals. We show here that distinct signaling pathways mediate the responses to touch and hyperosmolarity. ASH neurons distinguish between these stimuli because habituation to nose touch has no effect on the response to high osmolarity or volatile chemicals (1-octanol). Mutations in osm-10 eliminate the response to hyperosmolarity but have no effect on responses to nose touch or to volatile repellents. OSM-10 is a novel cytosolic protein expressed in ASH and three other classes of sensory neurons. Mutations in two other osmosensory-defective genes, eos-1 and eos-2, interact genetically with osm-10. Our analysis suggests that nose touch sensitivity and osmosensation occur via distinct signaling pathways in ASH and that OSM-10 is required for osmosensory signaling.

Amino Acid Sequence↗
PubMed2004

The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia.

The c-Jun N-terminal protein kinase (JNK) signaling pathway is implicated in neuronal apoptosis. The mechanism by which activated JNK induces neuronal apoptosis is strongly linked to mitochondrial apoptogenic proteins, although the molecular machinery downstream of JNK has not been precisely elucidated. Our study examined the relevance of proapoptotic Bcl-2 family members in JNK-mediated apoptosis after transient focal cerebral ischemia (tFCI), which, when induced by 60 min of middle cerebral artery (MCA) occlusion, elevated levels of JNK activity and phospho-JNK in the MCA territory. Phospho-JNK was primarily expressed in neurons and colocalized with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-positive cells. Inhibition of JNK activity by anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), a selective JNK inhibitor, protected neurons from ischemia-induced apoptosis detected by TUNEL staining and an apoptotic-related DNA fragmentation assay. SP600125 blocked translocation of the cell death effector Bax from the cytosol to the mitochondria after tFCI. BimL (Bim long) was induced and phosphorylated parallel to JNK activity. Coimmunoprecipitation studies consistently revealed increased interaction of JNK with BimL, as well as BimL with Bax, after tFCI. SP600125 blocked these interactions at a dose that significantly inhibited JNK-induced neuronal apoptosis. These results suggest that the JNK signaling pathway is involved in ischemia-induced neuronal apoptosis by stimulation, at least in part, of Bax translocation to the mitochondria, in which BimL is likely regulated by JNK as a downstream substrate for transmission of apoptotic signals to Bax.

Animals↗
PubMed1999

Disruption of gap junctional communication by the platelet-derived growth factor is mediated via multiple signaling pathways.

The platelet-derived growth factor (PDGF) mediates its cellular functions via activation of its receptor tyrosine kinase followed by the recruitment and activation of several signaling molecules. These signaling molecules then initiate specific signaling cascades, finally resulting in distinct physiological effects. To delineate the PDGF signaling pathway responsible for the disruption of gap junctional communication (GJC), wild-type PDGF receptor beta (PDGFRbeta) and a series of PDGFRbeta mutants were expressed in T51B rat liver epithelial cells. In cells expressing wild-type PDGFRbeta, PDGF induced disruption of GJC and phosphorylation of a gap junctional protein, connexin-43 (Cx43), which required activation of mitogen-activated protein kinase, although involvement of additional factors was also evident. In the F5 mutant lacking binding sites for phosphatidylinositol 3-kinase, GTPase-activating protein, SHP-2, and phospholipase Cgamma1 (PLCgamma1), PDGF induced mitogen-activated protein kinase, but failed to affect GJC or Cx43, indicating involvement of additional signals presumably initiated by one or more of the mutated binding sites. Examination of the single-site mutants revealed that PDGF effects were not mediated via a single signaling component. This was confirmed by the "add-back" mutants, which showed that restoration of either SHP-2 or PLCgamma1 binding was sufficient to propagate the GJC inhibitory actions of PDGF. Further analysis showed that activation of PLCgamma1 is involved in Cx43 phosphorylation, which surprisingly failed to correlate with GJC blockade. The results of our study demonstrate that PDGF-induced disruption of GJC can be mediated by multiple signaling pathways and requires participation of multiple components.

Animals↗
PubMed1999

Cytoskeletal reorganization leads to induction of the urokinase-type plasminogen activator gene by activating FAK and Src and subsequently the Ras/Erk signaling pathway.

Previously, we showed that cytoskeletal reorganization (CSR) induced by colchicine or cyochalasins leads to activation of the urokinase-type plasminogen activator (uPA) gene in LLC-PK(1) cells via the Ras/Erk signaling pathway [Irigoyen et al. (1997) J. Biol. Chem. 272, 1904]. It remained to be seen how CSR activates Ras/Erk signaling. Changes in cell morphology triggered by extracellular signals are often mediated by integrin-associated proteins, such as focal adhesion kinase (FAK) and Src. We found that CSR induced the activation of FAK and Src and the association of FAK and Shc, a signaling molecule linking growth factor receptor tyrosine kinase and Grb2. Furthermore, expression of either FRNK, a kinase-minus FAK-like molecule acting as a dominant negative FAK, or a dominant negative Src suppressed CSR-induced uPA gene promoter activation. These results suggest that cells respond to a morphology change, using the cytoskeleton as a sensor, by activating FAK and Src and subsequently the Ras/Erk signaling pathway.

Animals↗
PubMed1995

Functional conservation of the Wnt signaling pathway revealed by ectopic expression of Drosophila dishevelled in Xenopus.

Wnt genes encode secreted growth factors that exhibit potent effects on both embryonic and postembryonic development in vertebrates and invertebrates. Recently, the dishevelled (dsh), shaggy/zeste-white 3, and armadillo genes have been shown to participate in Wnt (wingless; wg) signaling in Drosophila. Vertebrate genes that have sequence similarities to all of these Drosophila genes have been identified. To determine whether these structurally conserved components of insect wg signaling represent a functionally conserved Wnt signaling pathway in vertebrates, we investigated the role of Drosophila dsh in Xenopus Wnt signaling. Xenopus embryos ectopically injected with Drosophila dsh mRNA developed duplicated axes similar to those seen in embryos injected with Wnt mRNAs. The involvement of dsh function in the Wnt signaling pathway in Xenopus was demonstrated using two assays which are specifically sensitive to Wnt signaling: synergistic induction of dorsal mesoderm with bFGF and the specific induction of a Wnt-responsive reporter gene. These findings support the notion that the intracellular response to the Wnt signal has been conserved during evolution to such an extent that its components may be interchanged between distantly related species.

Animals↗
PubMed1998

Signalling pathways involved in nicotine regulation of apoptosis of human lung cancer cells.

Although nicotine has been implicated as a potential factor in the pathogenesis of human lung cancer, its mechanism of action in the development of this cancer remains largely unknown. The present study provides evidence that nicotine (a) activates the mitogen-activated protein (MAP) kinase signalling pathway in lung cancer cells, specifically extracellular signal-regulated kinase (ERK2), resulting in increased expression of the bcl-2 protein and inhibition of apoptosis in these cells; and (b) blocks the inhibition of protein kinase C (PKC) and ERK2 activity in lung cancer cells by anti-cancer agents, such as therapeutic opioid drugs, and thus can adversely affect cancer therapy. Nicotine appears to have no effect on the activities of c-jun NH2-terminal protein kinase (JNK) and p38 MAP kinases, which have also been shown to be involved in apoptosis. While exposure to nicotine can result in the activation of the two major signalling pathways (MAP kinase and PKC) that are known to inhibit apoptosis, nicotine regulation of MAP (ERK2) kinase activity is not dependent on PKC. These effects of nicotine occur at concentrations of 1 microM or less, that are generally found in the blood of smokers, and could lead to disruption of the critical balance between cell death and proliferation, resulting in the unregulated growth of cells. The findings suggest caution in the use of smokeless tobacco products to treat smoking addiction, as they could have a potentially deleterious effect in patients with undetectable early tumour development.

Apoptosis↗
PubMed2006

Signaling pathway of morphine induced acute thermal hyperalgesia in mice.

Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 microg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCbeta3 at 2 nmol/mouse and PKCgamma at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCbeta3/PKCgamma/NMDA pathway stimulated by low concentrations of morphine, through muOR1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCbeta3 or PKCgamma at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.

Analgesia↗
PubMed2006

Targeting signaling pathways in multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of terminally differentiated B-cells accounting for approximately 1 to 2% of all human cancers. The development of MM is believed to be a multistep transformation process that leads to progressive accumulation of genetic alterations. The interaction between MM and bone marrow (BM) microenviroment triggers multiple proliferative and antiapoptotic signaling pathways. Here we discuss the current understanding of signaling pathways, and their potential implication in targeted therapies in MM.

Animals↗
PubMed2006

Signaling pathways involved in the cardioprotective effects of cannabinoids.

The aim of the present article is to review the cardioprotective properties of cannabinoids, with an emphasis on the signaling pathways involved. Cannabinoids have been reported to protect against ischemia in rat isolated hearts, as well as in rats and mice in vivo. Although these effects have been observed mostly with a pre-treatment of a cannabinoid, we report that the selective CB(2)-receptor agonist JWH133 is able to reduce infarct size when administered either before ischemia, during the entire ischemic period, or just upon reperfusion. Little is known about the signaling pathways involved in these cardioprotective effects. Likely candidates include protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) since they are activated during ischemia-reperfusion and contribute to the protective effect ischemic preconditioning. The use of pharmacological inhibitors suggests that PKC, p38 MAPK, and p42/p44 MAPK (ERK1/2) contribute to the protective effect of cannabinoids. In addition, perfusion with JWH133 in healthy hearts caused an increase in both p38 MAPK phosphorylation level and activity, whereas the CB(1)-receptor agonist ACEA was associated with an increase in the phosphorylation status of both ERK1 and ERK2 without any change in activity. During ischemia, both agonists doubled p38 MAPK activity, whereas ERK1/2 phosphorylation level and activity during reperfusion were enhanced only by the CB(1)-receptor agonist. Finally, although nitric oxide (NO) was shown to exert both pro and anti-apoptotic effects on cardiomyocytes, with an apparently controversial effect on myocardial survival, our data suggest that NO may contribute to the cardioprotective effect of some cannabinoids.

Animals↗
PubMed2000

beta1 integrin antagonism on adherent, differentiated human neuroblastoma cells triggers an apoptotic signaling pathway.

Integrin receptors mediate several functions including prevention of matrix detachment-induced apoptosis (anoikis) of several adherent cell types. We report here that antagonists of beta1 integrins trigger an apoptotic signaling pathway in adherent differentiated LAN-5 human neuroblastoma cells, a cell line which represents a model system for the study of human neurons. The pathway is characterized by cytochrome c release into the cytoplasm, and activation of caspase-9 and caspase-3, 4-6h after treatment; cleavage products of caspase-8 and caspase-2 were not detectable in the cells. Coordinate inactivation of cell survival pathways, including cleavage of focal adhesion kinase, decreased expression of protein kinase B, and reduced phosphorylation of the pro-apoptotic protein, Bad, also characterized the signaling pathway. These events occurred in adherent cells; DNA fragmentation and detachment followed as late events 18-24h after addition of beta1 integrin antagonists. zDEVD-fmk, an irreversible inhibitor of caspase-3-like enzymes, and cytochalasin D, an actin depolymerizing agent, blocked caspase-3 cleavage and delayed cell death. In contrast to these results, undifferentiated, adherent and dividing LAN-5 cells did not die in response to beta1 integrin antagonists. These studies identify a distinct apoptotic pathway which is triggered by antagonists of beta1 integrins on differentiated adherent neuronal cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

Axin: a master scaffold for multiple signaling pathways.

Axin was originally identified from the characterization of the Fused locus, the disruption of which leads to duplication of axis and embryonic lethality. It is a multidomain protein that interacts with multiple proteins and functions as a negative regulator of Wnt signaling by downregulating the beta-catenin levels. Recently, it was demonstrated that Axin also plays an important role in a JNK signaling pathway. Axin utilizes discriminatory domains for its distinct roles in the Wnt pathway and in the Axin/JNK pathway. Here we review the data that show how Axin regulates multiple signaling pathways by serving as a scaffold protein, controlling diverse cellular functions in proliferation, fate determination, and suppression of tumorigenesis.

Animals↗
PubMed2004

The paradox of the insulin/IGF-1 signaling pathway in longevity.

Ageing may be controlled by a genetic-hormonal system that may have originated from a very early common ancestor. One of the pathways that has been implicated in ageing is the insulin/insulin-like growth factor (IGF-1) signaling, which is involved in many functions that are necessary for metabolism, growth, and fertility in animal models like flies, nematodes, and mammalians. While disruption of the insulin/IGF-1 receptor in nematodes and flies increases lifespan significantly, mammals with genetic or acquired defects in insulin signaling pathway are at risk for age-related diseases and increased mortality. This contradiction can be explained by the acquisition of more complicated metabolic pathways in mammalians over evolution. Mammals have insulin/IGF-1 receptors in many organs, but their functions are opposite if they are located in the central nervous system or in the periphery; whereas lower species have insulin/IGF-1 receptors signaling mainly through the nervous system. Furthermore, mammalians have different and very specific receptors for insulin and IGF-1, with distinct pathways and diverse functions. Striking evidence suggests that decreased IGF-1 levels and signaling during early development, but not the insulin signaling may modulate longevity in many species. Thus, paradoxical outcomes follow the decrease of insulin and/or IGF-1 signal pathway in invertebrates and in mammals, prolonging life in the former and shortening it in the latter. In this review we focus on the downstream cascade of events in the insulin and IGF-1 signaling to identify specific pathways that are relevant to human longevity.

Animals↗
PubMed1996

Activation of Pyk2 by stress signals and coupling with JNK signaling pathway.

The c-Jun amino-terminal kinase (JNK) is activated by various heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors, inflammatory cytokines, and stress signals. Yet, upstream mediators that link extracellular signals with the JNK signaling pathway are currently unknown. The tyrosine kinase Pyk2 was activated by tumor necrosis factor alpha, by ultraviolet irradiation, and by changes in osmolarity. Overexpression of Pyk2 led to activation of JNK, and a dominant-negative mutant of Pyk2 interfered with ultraviolet light- or osmotic shock-induced activation of JNK. Pyk2 represents a cell type-specific, stress-sensitive mediator of the JNK signaling pathway.

Animals↗
PubMed1998

An assay method for evaluating chemical selectivity of agonists for insulin signaling pathways based on agonist-induced phosphorylation of a target peptide.

An optical method for evaluating the physiologically relevant agonist and antagonist selectivity of an insulin signaling pathway based on an insulin-dependent on/off switching of phosphorylation of a target peptide via insulin receptor is described. Insulin receptor serves as a binding for insulin and a given insulin receptor-binding peptide as a target for an insulin-receptor complex. Upon binding of insulin to its receptor, the insulin receptor undergoes autophosphorylation which enables the receptor to have a kinase activity and phosphorylate various substrates. The phosphorylated tyrosine in the substrate was measured with a monoclonal anti-phosphotyrosine antibody. As the target substrate for insulin receptor, a Y939 peptide consisting of 12 amino acid residues derived from insulin receptor substrate 1 (IRS-1) was used. The present assay method involves different sequential steps: (1) immobilization of a biotin-coupled Y939 peptide on an avidin coated 96-well plate via biotin-avidin complexation; (2) insulin-dependent phosphorylation of the Y939 peptide by the insulin receptor; (3) enzymatic reaction and absorptiometric assay of the phosphorylated Y939 peptide using the anti-phosphotyrosine antibody labeled with horseradish peroxidase. An insulin-dependent absorbance was observed for insulin concentrations from 1.0 x 10(-10) to 1.0 x 10(-7) M, and it leveled off. The observed absorbance was explained to be due to an increase in the phosphorylated Y939 peptide caused by insulin and its receptor complexation. No signal was, however, induced by both vanadyl and vanadate ions at concentrations up to 1.0 x 10(-4) M; these results and previous intact cell level data taken together led to the conclusion that these ions did not induce phosphorylation of the Y939 peptide. Upon addition of tyrphostin 25, a specific inhibitor for insulin receptor kinase activity, phosphorylation of the Y939 peptide in the presence of 1.0 microM insulin was competitively inhibited over 1.0 x 10(-4) M tyrphostin 25. The present system thus exhibited "physiologically more relevant" agonist and antagonist selectivity, the principle of which is based in part on the insulin signal transduction rather than simply relying on the binding assay. The potential use of the present method for evaluating the selectivity of a wide range of agonists and antagonists toward the insulin signaling pathways is discussed.

Amino Acids↗