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At least 343 records · Page 19Linked to original sources
PubMed2006

Pathophysiology defined by altered signal transduction pathways: the role of JAK-STAT and PI3K signaling in leukemic large granular lymphocytes.

Signal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. Thus, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.

CD8-Positive T-Lymphocytes↗
PubMed2006

Human tumor mutants in the p110alpha subunit of PI3K.

The PI3K-Akt pathway is frequently upregulated in human tumors. Recently, somatic mutations of PIK3CA, encoding p110alpha catalytic subunit of Class IA PI3Ks, have been found in various cancers. The two most common types of p110alpha mutants, those in the helical and kinase domains, have been shown to be very potent in Akt activation and oncogenic transformation by several groups. Notably these common mutations may not enhance recruitment of p110alpha to the plasma membrane where its substrates are located. We have investigated the effect of membrane localization on common PIK3CA tumor mutants via myristoylation. In addition we have studied a third class of less frequent mutants in the p85-binding domain, in an attempt to gain insight into p85's inhibitory effect on p110alpha. This article briefly reviews and extends the literature on mutant forms of p110alpha.

Class I Phosphatidylinositol 3-Kinases↗
PubMed1999

The complexities of CD28 and CTLA-4 signalling: PI3K and beyond.

A successful immune response requires a set of non-cognate cell-cell interactions which provide the second "costimulatory" signal to the T cells. The best characterized costimulatory receptor expressed on resting T cells is CD28 which provides poorly-defined cyclosporin-resistant biochemical signal(s) that promote expression of several cytokines/chemokines. Another major effect of CD28 ligation is the promotion of cell survival which is thought to occur via the up-regulation of Bcl-xL expression, CD28 shares its ligands B7.1 and B7.2 with the related CTLA-4, which plays an inhibitory role in T cell activation. Manipulation of CD28/CTLA-4 interactions with their natural ligands has provided exciting results in transplantation and tumor therapy settings and also has potential in the treatment of several diseases such as arthritis and multiple sclerosis, asthma and protection against HIV infection. The biochemical basis for the different functional outcomes of CD28 and CTLA-4 ligation has been the subject of intense investigation over the past few years. This review will focus on our current understanding of the biochemical signals that may be involved in regulating the different functional outcomes of CD28 and CTLA-4, with particular emphasis on the role played by the PI3K-dependent signalling cascade.

Abatacept↗
PubMed2006

Role of the insulin-like growth factor 1 (IGF1)/phosphoinositide-3-kinase (PI3K) pathway mediating physiological cardiac hypertrophy.

Growth of the heart can be induced by physiological stimuli (e.g. postnatal development or chronic exercise training: 'the athlete's heart') or pathological stimuli (e.g. pressure or volume overload). Physiological hypertrophy is characterized by the normal organization of sarcomeres and fibres, normal or enhanced cardiac function and a relatively normal pattern of cardiac gene expression; whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction and increased mortality. Previously, an unresolved question in cardiac biology was whether distinct signalling pathways are responsible for the development of pathological and physiological cardiac hypertrophy. Recent studies have identified several signalling pathways that play unique roles in the regulation of pathological and physiological cardiac hypertrophy. This review focuses largely on the role of the insulin-like growth factor 1 (IGF1)/phosphoinositide-3-kinase (PI3K) pathway in mediating physiological cardiac growth.

Animals↗
PubMed2006

[The anti-tumoral effect of PI3K inhibitor and MEK inhibitor combined with STI571 on chronic myeloid leukemia cells in a bone marrow stromal cell co-culture system].

The goal of this study was to elucidate the functional roles of PI3K/AKT and MEK/ERK signaling on the proliferation and apoptosis of STI571-sensitive and -resistant CML cell lines in a co-culture system with human marrow stromal cells (MSCs), mimicking the bone marrow microenvironment. The phosphorylation of AKT and ERK was enhanced by co-culture with MSCs in both STI571-sensitive KBM-5 and STI571-resistant KBM-5/STI cells. In KBM-5 cells, the STI571 and PI3K inhibitor LY294002 combination was effective on apoptosis induction in the MSC co-culture system. In KBM-5/STI cells, treatment with LY294002 or PD98059 alone resulted in massive apoptosis, which was enhanced by co-culture with MSCs. These results provide a rationale for multi-molecular target therapy approaches based on a combination of signal transduction inhibitors with STI571 in CML.

Antineoplastic Agents↗
PubMed2000

Rapid lamellipodia formation in nerve growth factor-stimulated PC12 cells is dependent on Rac and PI3K activity.

Neuronal differentiation of PC12 cells is achieved by stimulation with nerve growth factor (NGF) but not by epidermal growth factor (EGF). However, features of differentiation such as neurite outgrowth are observable at the earliest after several hours. Using actin staining of the cells, we show here that NGF stimulation leads to lamellipodia formation within only 3 min at the periphery of the PC12 cells. EGF stimulation or microinjection of differentiation-inducing c-Crk I protein does not cause lamellipodia. The actin reorganization after NGF stimulation is blocked by microinjecting dominant negative Rac protein. The lamellipodia formation is also abolished by inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY 294002 in a concentration-dependent manner. Phase-contrast time-lapse microscopy was used to analyze membrane dynamics in real time and to confirm the induction of lamellipodia by NGF and their inhibition by pretreatment with both wortmannin and LY 294002. The results indicate that NGF, but not EGF, leads to rapid lamellipodia formation in PC12 cells via phosphatidylinositol 3-kinase and the small GTPase Rac, thereby defining a novel role for these factors in early NGF signaling.

Androstadienes↗
PubMed2006

Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K.

The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-kappaB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis.

Animals↗
PubMed2005

Independent role of phosphoinositol-3-kinase (PI3K) and casein kinase II (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells.

BACKGROUND: Recent research has highlighted the potential role of EGFR and Her-2 in the constitutive activation of NF-kappaB (NF-kappaB) in prostate cancer cells, although the mechanism by which these receptors activate NF-kappaB in these cells remains unclear. METHODS AND RESULTS: Using pharmacological and genetic approaches we show that in PC-3 cells, EGFR and Her-2 are involved in the constitutive activation of NF-kappaB through two different mechanisms. EGFR activates NF-kappaB through the PI3K/Akt pathway that leads to the phosphorylation of IkappaBalpha on serines 32 and 36, thereby promoting the nuclear translocation of the p65 subunit. In contrast, Her-2 activates NF-kappaB through Casein Kinase II (CK-2) activation independently of IkappaBalpha phosphorylation on serines 32 and 36. CONCLUSIONS: Our study not only directly clarifies the signaling pathways involved in NF-kappaB activation in prostate cancer cell lines and but also provides a framework for further studies in the clinical characterization and management of prostate cancer.

Blotting, Western↗
PubMed2005

Inhibition of the PI3K pathway sensitizes fludarabine-induced apoptosis in human leukemic cells through an inactivation of MAPK-dependent pathway.

In the present study, we have investigated the effects of PI3K/Akt pathway on the response of human leukemia cells to fludarabine. Inhibition of PI3K/Akt pathway with a selective inhibitor (e.g., LY294002, or wortmannin) in leukemic cells markedly potentiated fludarabine-induced apoptosis. Inhibition of the PI3K/Akt downstream target mTOR by rapamycin also significantly enhanced fludarabine-induced apoptosis. The co-treatment of fludarabine/LY294002 resulted in significant attenuation in the levels of both phospho-Erk1/2 and phospho-Akt, as well as a marked increase in the level of phospho-JNK. The broad spectrum caspase inhibitor BOC-D-fmk markedly blocked fludarabine/LY-induced apoptosis, had no effect on cytochrome c release to the cytosol, and did abrogate caspase and PARP cleavage. This indicates that mitochondrial dysfunction is upstream of the caspase cascade. Moreover, constitutive activation of the MEK/Erk pathway completely blocked apoptosis induced by the combination of fludarabine/LY294002. Additionally, either constitutive activation of Akt or blockage of the JNK pathway significantly diminished apoptosis induced by the combination. Collectively, these findings demonstrate that inactivation of MAPK, Akt, and activation of the JNK pathway contributes to the induction of apoptosis induced by fludarabine/LY. Comparatively, MAPK inactivation plays a crucial role in fludarabine/LY-induced apoptosis. These results also strongly suggest that combining fludarabine with an inhibitor of the PI3K/Akt/mTOR pathway may represent a novel therapeutic strategy for hematological malignancies.

Apoptosis↗
PubMed2006

Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1.

LEOPARD (LS) and Noonan (NS) are overlapping syndromes associated with distinct mutations of SHP-2. Whereas NS mutations enhance SHP-2 catalytic activity, we show that the activity of three representative LS mutants is undetectable when assayed using a standard protein tyrosine phosphatase (PTP) substrate. A different assay using a specific SHP-2 substrate confirms their decreased PTP activity, but also reveals a significant activity of the T468M mutant. In transfected cells stimulated with epidermal growth factor, the least active LS mutants promote Gab1/PI3K binding, validating our in vitro data. LS mutants thus display a reduced PTP activity both in vitro and in transfected cells.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Pitavastatin at low dose activates endothelial nitric oxide synthase through PI3K-AKT pathway in endothelial cells.

Pitavastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that is used for suppressing cholesterol biosynthesis. Previously, we have reported that pitavastatin induces the activation of endothelial nitric oxide synthase (eNOS) and increases nitric oxide (NO) production in vascular endothelial cells (EC). However, the mechanism of eNOS activation by pitavastatin remains unknown. Here, we examined the implications of pitavastatin-induced signaling in eNOS phosphorylation in EC. We found that treatment of EC with a low dose of pitavastatin induced eNOS phosphorylation at Ser-1177, activated Akt phosphorylation at Ser-473 in a time-and dose-dependent manner, and increased NO production. These processes were suppressed by the addition of either mevalonic acid (MEV) or geranylgeranyl pyrophosphate (GGPP). In addition, northern blot analysis revealed that pitavastatin did not increase eNOS mRNA expression level in EC. These results suggest that the activation of eNOS with a low dose of pitavastatin (0.1 microM) involves phosphoinositide 3-kinase and the Akt pathway and produces NO in EC, which is dependent on post-transcriptional regulation. This pathway is critical for cellular responses that contribute to EC function.

Blotting, Northern↗
PubMed2005

Cytokines secreted by bone-metastatic breast cancer cells alter the expression pattern of f-actin and reduce focal adhesion plaques in osteoblasts through PI3K.

Breast cancer frequently metastasizes to bone, resulting in osteolytic lesions. These lesions, formed by activated osteoclasts, cause pain, an increased susceptibility to fractures, and hypercalcemia. It has been shown that breast cancer cells communicate with osteoblasts and subsequently stimulate osteoclast activity; however, little research has focused on understanding the interaction between breast cancer cells and osteoblasts. We recently reported that conditioned medium from MDA-MB-231 breast cancer cells inhibited the differentiation of MC3T3-E1 osteoblasts through the secretion of transforming growth factor beta (TGFbeta). In addition, the breast cancer conditioned medium altered MC3T3-E1 morphology, the pattern of actin stress fibers, and reduced focal adhesion plaques. In the current study, we identified the mechanism used by MDA-MB-231 cells to cause these effects. When MC3T3-E1 osteoblasts were cultured with MDA-MB-231 conditioned medium preincubated with neutralizing antibodies to platelet derived growth factor (PDGF), insulin-like growth factorII (IGFII), and TGFbeta, focal adhesion plaques and actin stress fiber formation were restored. These cytokines were further found to signal through PI3Kinase and Rac. In conclusion, TGFbeta, PDGF, and IGFII might be good therapeutic targets for treating breast cancer-induced osteolytic lesions.

Actins↗
PubMed2001

Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts.

Focal adhesion kinase (FAK) is a key mediator of integrin signaling, which has been implicated in the regulation of cell migration and cell cycle progression. Using chimeric molecules that fuse the focal adhesion targeting (FAT) sequence directly to several signaling molecules, we investigated the potential role of FAK recruitments of signaling molecules to focal contacts in the regulation of cell migration and cell cycle progression. We found that fusion of FAT to Src, the p85 subunit of phosphatidylinositol 3-kinase, Grb7 and Grb2 resulted in the efficient focal adhesion targeting of these signaling molecules. We showed that expression of Src-FAT, p85-FAT, or Grb7-FAT, but not Grb2-FAT, each stimulated cell migration. Interestingly, tyrosine phosphorylation of paxillin, but not p130cas, was induced by expression of Src-FAT, suggesting a potential role of paxillin in mediating stimulation of cell migration by the chimeric molecule. In contrast, targeting of Grb2, but not Src, p85, or Grb7, to focal contacts increased cell cycle progression. Biochemical analyses correlated Erk activation by Grb2-FAT with its stimulation of cell cycle progression. Together, these results suggest that at least part of the role of FAK interaction with these signaling molecules is to recruit them to focal contacts and that distinct FAK signaling complexes are involved in the regulation of cell migration vs. cell cycle progression.

3T3 Cells↗
PubMed1999

p68 Sam is a substrate of the insulin receptor and associates with the SH2 domains of p85 PI3K.

The 68 kDa Src substrate associated during mitosis is an RNA binding protein with Src homology 2 and 3 domain binding sites. A role for Src associated in mitosis 68 as an adaptor protein in signaling transduction has been proposed in different systems such as T-cell receptors. In the present work, we have sought to assess the possible role of Src associated in mitosis 68 in insulin receptor signaling. We performed in vivo studies in HTC-IR cells and in vitro studies using recombinant Src associated in mitosis 68, purified insulin receptor and fusion proteins containing either the N-terminal or the C-terminal Src homology 2 domain of p85 phosphatidylinositol-3-kinase. We have found that Src associated in mitosis 68 is a substrate of the insulin receptor both in vivo and in vitro. Moreover, tyrosine-phosphorylated Src associated in mitosis 68 was found to associate with p85 phosphatidylinositol-3-kinase in response to insulin, as assessed by co-immunoprecipitation studies. Therefore, Src associated in mitosis 68 may be part of the signaling complexes of insulin receptor along with p85. In vitro studies demonstrate that Src associated in mitosis 68 associates with the Src homology 2 domains of p85 after tyrosine phosphorylation by the activated insulin receptor. Moreover, tyr-phosphorylated Src associated in mitosis 68 binds with a higher affinity to the N-terminal Src homology 2 domain of p85 compared to the C-terminal Src homology 2 domain of p85, suggesting a preferential association of Src associated in mitosis 68 with the N-terminal Src homology 2 domain of p85. This association may be important for the link of the signaling with RNA metabolism.

Adaptor Proteins, Signal Transducing↗