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PubMed1996

Insulin and ATP stimulate actin polymerization in U937 cells by a wortmannin-sensitive mechanism.

ATP and insulin stimulate increases in phosphatidylinositol (3,4,5)-trisphosphate levels in myeloid-derived U937 cells. Quantification of FITC-phalloidin binding by fluorescence-activated cell sorting reveals that both ATP and insulin stimulate actin polymerization with distinctive kinetics in U937 cells. The response to ATP is rapid and dose-dependent with an EC50 of 200 nM, and is abolished by pre-incubation with the Ca2+ chelator BAPTA-AM. At 800 nM concentration, wortmannin, a potent inhibitor of phosphoinositide 3-kinase (PI3K), blocks the late, but not the early phase of actin polymerization stimulated by 100 nM ATP. Responses elicited by 10 micrograms/ml insulin are slower, smaller and more transient than responses to ATP, and are inhibited by preincubation with 100 nM wortmannin. Actin polymerization can also be stimulated by thapsigargin, but not by phorbol ester, providing further evidence for a role for Ca2+ in actin polymerization. These data implicate distinct Ca2+ and PI3K-mediated pathways in the regulation of actin polymerization.

Actins↗

PubMed2004

Augmentation of lipolysis in adipocytes from fed rats, but not from starved rats, by inhibition of rolipram-sensitive phosphodiesterase 4.

The sensitivity of adipocytes to lipolytic agents is increased after starvation. In this study, we found that LY294002, an inhibitor of phosphatidylinositol-3 kinase (PI3K), in the concentration of more than 50 microM potentiates lipolysis induced by adenosine deaminase in adipocytes from fed rats (f-adipocytes), but not from starved rats (s-adipocytes). It also enhanced the sensitivity to lipolytic action of isoproterenol in f-adipocytes much more than s-adipocytes. The target of LY294002 may be an anti-lipolytic regulator expressed in response to food intake. Since another PI3K inhibitor, wortmannin, or a phosphodiesterase 3 (PDE3) inhibitor, cilostamide, failed to cause any specific effect to f-adipocytes, the PI3K-PDE3B pathway cannot be a target of LY294002. We found that LY294002 inhibits efficiently the cytoplasmic PDE activity of adipocytes. Rolipram, a specific inhibitor of PDE4, also inhibited the cytoplasmic PDE and caused a preferential increase of lipolysis in f-adipocytes. LY294002 blunted the actions of rolipram on lipolysis and the PDE activity. LY294002 accelerated protein kinase A activation. These data suggest that the rolipram-sensitive PDE4 is an anti-lipolytic enzyme expressed according to food intake. LY294002 may potentiate lipolysis through inhibition of the PDE4.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Tryptase activates PKB in inflammatory reaction in ECV304 cells.

Tryptase is involved in proteinase-activated receptor-2 (PAR-2) mediated up-regulation of IL-8 expression. The present report showed the effects of tryptase on gene expression and activation, including up-regulation IL-8 expression. The expression of mRNA for NF-kappaB first increased at 1 h after tryptase-treatment (1 ng/ml) and reached the plateau after 4 h. The NF-kappaB mRNA increased by 3-fold (n = 3, P < 0.05), AP-1 by 2-fold (n = 3, P < 0.05), and PKB by 10-fold (n = 3, P < 0.05). However, tryptase-treatment did not affect the expression of JNK and p38 MAPK when compared with control cells at mRNA level. Furthermore, in addition to increasing phosphorylation of p38 MAPK, tryptase-treatment also increased phosphorylation of PKB by 2-fold at 15 min following the treatment. The up-regulation and phosphorylation of PKB by tryptase could be abolished by either phosphoinositol-3-kinase (PI3K) inhibitor (LY294002) at 10 microM or antisense PKB cDNA transfection. The up-regulation of NF-kappaB expression could be inhibited by LY294002 and antisense PKB cDNA. These results indicate that tryptase can activate PI3K-PKB pathway and enhance IL-8 expression.

Cells, Cultured↗

PubMed2004

Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor.

In the present study, we investigated the effect of leptin on proliferation of hepatic stellate cells (HSCs) in vitro. Proliferation of 3-day cultured rat HSCs was assessed by incorporation of 5-bromo-2'-deoxyuridine (BrdU) into the nuclei. The percentages of BrdU-positive cells were increased in the presence of PDGF-BB (5 ng/ml) for 8h as expected. Co-incubation with leptin (10-100 nM) potentiates this PDGF-dependent increase in BrdU positive cells in a dose-dependent manner. Messenger RNA for PDGF receptor alpha and beta subunits was increased almost 2- to 3-fold by incubation with leptin for 6h. Further, pre-incubation with leptin for 6h enhanced PDGF-induced increases in phospho-p44/42 MAP kinase and phospho-Akt levels in a dose-dependent manner. In the same condition, however, leptin per se did not increase phospho-STAT 3 and phospho-p44/42 MAP kinase levels. Instead, leptin increased phospho-Akt levels in HSCs within 30 min, suggesting that the phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in the mechanism by which leptin accelerates the proliferation of HSCs. In conclusion, the present study clearly indicated that leptin potentiates PDGF-dependent proliferative responses of HSCs in vitro.

Animals↗

PubMed2006

Thrombin/thrombin receptor (PAR-1)-mediated induction of IL-8 and VEGF expression in prostate cancer cells.

Interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) are two cytokines promoting prostate tumor growth and angiogenesis. The main coagulation protease thrombin may modulate the malignant phenotype of prostate cancer cells via its cellular receptor(s). We aimed to investigate the effects of thrombin on IL-8 and VEGF expression in DU 145 prostate cancer cells. Thrombin induced the expression and secretion of IL-8 and VEGF, with more pronounced effects on IL-8. Target-specific siRNA-induced protease-activated receptor 1 (PAR-1) knockdown completely neutralized thrombin-enhanced cytokine secretion, demonstrating the essential role of PAR-1. Inhibitors of either extracellular signal-regulating kinase (ERK) or phosphatidylinositol 3-kinase (PI3K) partly reversed the thrombin-induced cytokine expression, suggesting that both ERK and PI3K kinase pathways may be involved in IL-8 and VEGF expression. The results suggest that the thrombin/PAR-1 system upregulates cytokines in prostate cancer cells which in turn may contribute to the progression of prostate cancer.

Extracellular Signal-Regulated MAP Kinases↗

PubMed2006

Induction of interleukin-8 secretion and activation of ERK1/2, p38 MAPK signaling pathways by thrombin in dermal fibroblasts.

It was reported that thrombin could induce IL-8 secretion from human dermal fibroblasts (HDFs) through activation of proteinase activated receptor (PAR)-1. However, little is known of intracellular signaling pathways involved in the event. In the present study, expression of PARs in primarily cultured HDFs was determined by flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR), levels of IL-8 were determined by using ELISA and signaling pathways were examined by using Western blot. It was found that HDFs express PAR-1 and PAR-3, and thrombin induces approximately 7.4-fold increase in IL-8 secretion from HDFs. Hirudin and a PAR-1 blocking antibody completely abolish the action of thrombin. It was also found that PD98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor and U0126, an inhibitor of extracellular signal-regulated kinase (ERK) blocks thrombin-induced phosphorylation of ERK1/2 and IL-8 secretion, indicating the involvement of MAPK/ERK signaling pathway in thrombin-induced IL-8 secretion. p38 MAPK pathway appears also being involved as SB203580, a selective inhibitor of p38 MAPK inhibit phosphorylation of p38 MAPK and thrombin-induced IL-8 secretion. Furthermore, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, but not phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway may also be activated by thrombin. In conclusion, thrombin potently induce IL-8 release via PAR-1 from HDFs. Thrombin elicited IL-8 release is predominantly conducted through MAPK/ERK and p38 MAPK signaling pathways. Discovery of the signaling pathways of thrombin in HDFs may help to understand the role of thrombin in inflammation and tissue remodeling.

Adolescent↗

PubMed2006

Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts.

Transforming growth factor-beta (TGF-beta) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/anti-apoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-beta1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-beta1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-beta1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-beta1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-beta1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these pro-survival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-beta1 in tissue fibrosis and tumour-promotion.

Animals↗

PubMed2006

Coculture with endothelial cells enhances vascular smooth muscle cell adhesion and spreading via activation of beta1-integrin and phosphatidylinositol 3-kinase/Akt.

The interactions between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) play significant roles in the homeostasis of the blood vessel during vascular remodeling. Cell adhesion and spreading are an essential process for VSMC migration, survival and proliferation in the events of vascular physiology and pathophysiology. However, effects of ECs on adhesion and spreading of VSMCs have not been characterized yet. Here, the interaction of ECs and VSMCs on adhesion and spreading of VSMCs were investigated by using a coculture system. The results showed that VSMCs cocultured with ECs exhibited a significant increase in the number of adherent and spreading cells, and much more mRNA (twofold, P<0.01) and protein (threefold, P<0.05) expression of beta(1)-integrin comparing to the control, i.e., VSMCs cultured alone. Furthermore, the enhanced functional activity of beta(1)-integrin expression was confirmed by FACS. A beta(1)-integrin blocking antibody (P5D2) could inhibit the EC-induced VSMC adhesion and spreading. It was demonstrated that in correspondence with enhanced cell adhesion, ECs also prompted focal adhesion complex assembly and stress fiber formation of VSMCs. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was more pronouncedly activated in response to VSMC attachment. Our results for the first time show that coculture with ECs enhances VSMC adhesion and spreading by up-regulating beta(1)-integrin expression and activating the PI3K/Akt pathway, suggesting that the interaction between ECs and VSMCs serves an important role in vascular homeostasis and remodeling.

Cell Adhesion↗

PubMedDate not supplied

Carbamazepine enhances the activity of glutamate transporter type 3 via phosphatidylinositol 3-kinase.

Glutamate transporters (also called excitatory amino acid transporters, EAAT) participate in maintaining extracellular homeostasis of glutamate, a major excitatory neurotransmitter, and regulating glutamate neurotransmission. EAAT3, the major neuronal EAAT, may also regulate gamma-aminobutyric acid-mediated inhibitory neurotransmission. Dysfunction of EAAT3 has been shown to induce seizure in rats. We hypothesize that carbamazepine, a commonly used antiepileptic agent, enhances EAAT3 activity. We tested this hypothesis using oocytes artificially expressing EAAT3 and C6 rat glioma cells expressing endogenous EAAT3. In oocytes, carbamazepine dose-dependently enhanced EAAT3 activity. The EC50 of this carbamazepine effect was 12.2muM. The concentrations of carbamazepine to significantly enhance EAAT3 activity were within the therapeutic serum levels (17-51muM) of carbamazepine for the antiepileptic effect. Carbamazepine decreased the Km but did not change the maximal response of EAAT3 to glutamate. Carbamazepine-increased EAAT3 activity was inhibited by wortmannin or LY-294002, phosphatidylinositol 3-kinase (PI3K) inhibitors, but was not affected by staurosporine, chelerythrine or calphostin C, protein kinase C inhibitors. In C6 cells, carbamazepine also enhanced the endogenous EAAT3 activity. However, carbamazepine did not affect the activity of EAAT4 expressed in Cos7 cells. These results suggest that carbamazepine at clinically relevant concentrations specifically enhances the affinity of EAAT3 for glutamate to increase EAAT3 activity via a PI3K-dependent pathway. EAAT3 may be a therapeutic target for carbamazepine in the central nervous system.

Animals↗

PubMed2006

Role of CDK5 in neuroprotection from serum deprivation by mu-opioid receptor agonist.

Cyclin-dependent kinase 5 (CDK5), a unique member of the CDK family of cyclin-dependent kinases, is predominantly expressed in postmitotic neurons with proposed roles in both cell survival and programmed cell death. To understand how CDK5 participates in such disparate cellular outcomes, we investigated whether activation of CDK5 could mediate neuroprotection from serum deprivation by mu-opioid receptor agonist in differentiated SH-SY5Y cells and primary hippocampal neurons. We found that CDK5 kinase activity decreased following serum deprivation in differentiated SH-SY5Y cells coincident with increased cell loss and activation of caspases cascade activation, which was reversed by opioid antagonist. Overexpression of CDK5 in serum-free medium reversed activation of caspase cascade and augmented DAMGO neuroprotection. Blocking CDK5 activity by pharmacologic inhibitor, roscovitine or overexpression of dominant negative CDK5 augmented activation of cell death markers and diminished mu-opioid receptor agonist protection. Reduction in CDK5 activity corresponded to reduction in protein levels of CDK5 activator p35 during serum deprivation which was also reversed by mu-opioid receptor agonist. Phosphorylation of STAT3 at Serine 727 by CDK5 decreased during serum deprivation, and partly recovered by mu-opioid agonist. PI3K signaling pathway was not required for CDK5-mediated mu-opioid neuroprotection against serum deprivation. These findings indicate that neuroprotection by mu-opioid receptor agonist against serum deprivation is mediated by activation of CDK5 through up-regulation of p35 and phosphorylation of STAT3 by CDK5 may contribute to the neuroprotection.

Animals↗

PubMed2004

Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase.

To investigate additional functions of the T cell adaptor, Src homology 2 (SH2) domain-containing leukocyte protein of 76 kD (SLP-76), we performed a yeast two-hybrid assay using the N-terminal region of SLP-76 fused with the kinase domain of Syk. By screening a human leukemia cDNA library, we identified the p85 subunit of phosphoinositide 3-kinase (PI3K) as one of the interacting molecules. Unlike the SH2 domain of Vav or Nck, tyrosine phosphorylation of SLP-76 at position 113 or 128 was sufficient for it to associate with the N-terminal SH2 of p85. Collectively, these data suggest that SLP-76 may play a role in PI3K signaling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.

Smad ubiquitination regulatory factor 2 (Smurf2), a ubiquitin ligase for Smads, plays critical roles in the regulation of transforming growth factor-beta (TGF-beta)-Smad signaling via ubiquitin-dependent degradation of Smad2 and Smad7. We found that TGF-beta stimulates Smurf2 expression. TGF-beta activated the Smurf2 promoter in a TGF-beta responsive cell lines, whereas IL-1alpha, PDGF and epidermal growth factor did not. TGF-beta-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor-like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad-binding elements in the promoter. Moreover, inhibition of the phosphatidil inositol 3 kinase (PI3K)/Akt pathway suppressed TGF-beta-mediated Smurf2 induction. These results suggest that TGF-beta stimulates Smurf2 expression by Smad-independent pathway such as PI3K/Akt pathway via TGF-beta receptor.

Blotting, Western↗

PubMed2006

IL-4 enhances hypoxia induced HIF-1alpha protein levels in human transformed intestinal cells.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that mediates the adaptive response to hypoxia. Increasing evidence suggests a crucial role for HIF-1 in immune reactions. Here we investigated the effect of the Th2 type cytokines IL-4 and IL-10 on HIF-1alpha mediated response in normoxia (21% O2) and hypoxia (1% O2). Incubation of human transformed intestinal cells (HT-29) with IL-4 significantly increased HIF-1alpha protein levels during hypoxia but not during normoxia. Mechanisms involved are IL-4 induced up-regulation of HIF-1alpha gene transcription and the PI3K signaling pathway. The increase in hypoxia-induced accumulation of HIF-1alpha protein after IL-4 treatment did not result in up-regulation of HIF-1 DNA-binding activity or HIF-1 dependent gene expression. IL-10 did not affect HIF-1alpha protein levels.

Cell Hypoxia↗

PubMed2006

Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy.

The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer.

Angiogenesis Inhibitors↗

PubMed2005

Lineage-specific requirement for the PH domain of Vav1 in the activation of CD4+ but not CD8+ T cells.

Vav1 is a guanine nucleotide exchange factor (GEF) for Rho-family GTPases, which is activated by tyrosine phosphorylation following TCR stimulation. Vav1-deficient mice have defects in positive and negative selection of thymocytes as well as TCR-induced proliferation in mature T cells, demonstrating a critical role for Vav1 in transducing TCR signals. Binding of phospholipids to the PH domain of Vav1 has been proposed to regulate its GEF activity in vitro. To test this model in vivo, we have generated mice carrying a point mutation in the PH domain of Vav1, and we show that they have defects in T cell development and activation. We demonstrate that the mutation affects the function of Vav1 as a GEF and perturbs PI3K-dependent pathways downstream of Vav1. Unexpectedly, the mutation selectively affects TCR-induced proliferation of CD4(+) but not CD8(+) T cells, demonstrating differences in the wiring of TCR signaling pathways between the two lineages.

Animals↗

PubMed2005

An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model.

Phosphoinositide 3-kinase (PI3K) exhibits broad functional effects in immune cells. We investigated the role of PI3K in allergic airway inflammation using LY294002, a specific PI3K inhibitor, in a mouse asthma model. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and developed airway eosinophilia, mucus hypersecretion, elevation in cytokine levels, and airway hyperresponsiveness. Intratracheal administration of LY294002 significantly inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13, and eotaxin levels in bronchoalveolar lavage fluid. Histological studies show that LY294002 dramatically inhibited OVA-induced lung tissue eosinophilia and airway mucus production. In addition, LY294002 significantly suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates shows that LY294002 markedly attenuated OVA-induced serine phosphorylation of Akt, a direct downstream substrate of PI3K. Taken together, our findings suggest that inhibition of PI3K signaling pathway can suppress T-helper type 2 (Th2) cytokine production, eosinophil infiltration, mucus production, and airway hyperresponsiveness in a mouse asthma model and may have therapeutic potential for the treatment of allergic airway inflammation.

Animals↗

PubMed2026

Lipid transfer proteins and PI4KIIα generate a phosphoinositide-linked proteome.

Phosphoinositide (PIPn) lipid second messengers in membranes regulate numerous cellular processes. In the cytosol, the phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway is scaffolded on IQGAP1 to facilitate the activation of Akt by the synthesis of PI3,4,5P3. In the nucleus, PIPn signaling occurs in compartments separate from membranes by stably linking PIPns to nuclear proteins. While several of these proteins have been identified, understanding the extent and impact of protein-linked PIPn signaling warrants further investigation. The tumor suppressor p53, was shown in the companion paper to be regulated by PI transfer proteins (PITPs) and a PI 4-kinase (PI4KIIα), which are required to form p53-PIPn complexes that assemble a nuclear PI3K/Akt pathway. Here we report that class I PITPs (PITPα/β) and PI4KIIα initiate PIPn linkages to many different proteins. PITPα/β and PI4KIIα accumulate in the nucleoplasm in response to stress and are necessary to synthesize nuclear PIPns linked to proteins. These PITPα/β-dependent protein-PIPn complexes are detected by metabolically labeling cells with the PIPn precursor [3H]-myo-inositol and resist denaturation and SDS-PAGE, indicating that these protein-PIPn complexes represent a putative posttranslational modification. Proteomic and gene set enrichment analysis of proteins that are linked to PI4,5P2 reveals an emerging PIPn-linked proteome (PIPylome) regulated by PITPα/β and enriched in proteins that play key functional roles in metabolism, cell motility/division, and the DNA damage response. The PIPn-linked proteome represents a third messenger signaling paradigm distinct from the canonical membrane-localized pathway whereby linked PIPn messengers regulate protein function.

Phosphatidylinositols↗

PubMed2026

IGF2BP1-Mediated m⁶A Modification Stabilizes HMGA2 mRNA to Promote Intrahepatic Cholangiocarcinoma Progression.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) remains a lethal malignancy with a lack of effective therapies, underscoring the critical need to identify novel therapeutic targets. The high-mobility group protein A2 (HMGA2) is an oncogenic architectural transcription factor aberrantly overexpressed in multiple cancers; yet its function and regulatory mechanisms in iCCA are poorly defined. This study aimed to elucidate the clinical significance and molecular mechanism of HMGA2 in iCCA progression. METHODS: We integrated analyses across 4 independent iCCA cohorts (The Cancer Genome Atlas, 2 Zhongshan Hospital cohorts, and our 192-patient institutional cohort). Functional investigations were conducted using iCCA cell lines and multiple mouse models, including xenograft, syngeneic, YAP/AKT-driven spontaneous iCCA, and metastasis models. RESULTS: We demonstrated that HMGA2 was significantly upregulated in iCCA, correlating with poor survival, and exhibited sexually dimorphic prognostic effects with a female-specific link to perineural invasion. Functionally, HMGA2 depletion suppressed iCCA cell proliferation, migration, in vivo tumor growth and metastasis. Mechanistically, HMGA2 expression was positively regulated by the N6-methyladenosine reader insulin-like growth factor 2 messenger RNA-binding protein 1 (IGF2BP1), which directly bound to and stabilized HMGA2 messenger RNA via its KH3-4 domains in an N6-methyladenosine-dependent manner. High IGF2BP1 expression predicted poor iCCA prognosis, was required for HMGA2-driven progression, and the axis promoted PI3K-AKT pathway activation. CONCLUSIONS: Our results reveal a critical role for the IGF2BP1-HMGA2 axis in iCCA pathogenesis, thereby highlighting its potential as a therapeutic target.

Cholangiocarcinoma↗