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PubMed2001

Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells.

Interleukin (IL)-6, a multifunctional regulator of immune response, hematopoiesis, and acute phase reactions, has also been shown to regulate cancer cell proliferation. We have investigated IL-6 signaling pathways and cellular responses in the T47D breast carcinoma cell line. The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and increased cell migration. In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration. IL-6 treatment led to activation of the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase (PI3K) pathways. Inhibition of MAPK or PI3K activity reversed IL-6- and oncostatin M-stimulated migration. Because cross-talk between cytokine receptors and members of the ErbB family of receptor tyrosine kinases has been described previously, we have examined their interaction in T47D cells. Down-regulation of ErbB receptor activity, through the use of specific pharmacological inhibitors or dominant negative receptor constructs, revealed that IL-6-induced MAPK activation was largely dependent on epidermal growth factor (EGF) receptor activity, but not on ErbB-2 activity. Using a monoclonal antibody that interferes with EGF receptor-ligand interaction, we have shown that in T47D cells, IL-6 cooperates with an EGF receptor autocrine activity loop for signaling through the MAPK and PI3K pathways and for cell migration. Both the tyrosine phosphatase SHP-2 and the multisubstrate docking molecule Gab1, which are potential links between IL-6 and the MAPK/PI3K pathways, were constitutively associated with the active EGF receptor. On IL-6 stimulation, SHP-2 and Gab1 were recruited to the gp130 subunit of the IL-6 receptor and tyrosine phosphorylated, allowing downstream signaling to the MAPK and PI3K pathways. Thus, in T47D breast carcinoma cells, IL-6 acts in synergy with EGF receptor autocrine activity to signal through the MAPK/PI3K pathways. Cooperation between IL-6 and the EGF receptor in T47D breast carcinoma cells illustrates how a combination of multiple stimuli, either exogenous or endogenous, may result in synergistic cellular responses.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta.

Although the class I(A) phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin, its mechanism of action is not well understood. To identify the role of the PI3K pathway in insulin regulation of hepatic function, we ablated the expression of both major regulatory subunits of PI3K by crossing mice lacking Pik3r1 in liver with Pik3r2 null mice, creating liver-specific double knockout mice (L-p85DKO). L-p85DKO mice failed to activate PI3K or generate PIP(3) upon insulin stimulation or activate its two major effectors, Akt and PKClambda/xi. Decreased Akt activation resulted in increased gluconeogenic gene expression, impaired glucose tolerance, and hyperinsulinemia, while the defective activation of PKClambda/xi by insulin was associated with hypolipidemia and decreased transcription of SREBP-1c. These data indicate that the PI3K pathway is critical for insulin's actions in the liver in vivo, and that differential regulation by Akt and PKClambda/xi differentially defines specific actions of insulin and PI3K on hepatic glucose and lipid metabolism.

Adipose Tissue↗
PubMed2024

Polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA) are associated with the PI3K-AKT pathway activation.

AIMS: We aimed to elucidate the mechanism leading to polycystic ovarian syndrome (PCOS) and recurrent spontaneous abortion (RSA). BACKGROUND: PCOS is an endocrine disorder. Patients with RSA also have a high incidence rate of PCOS, implying that PCOS and RSA may share the same pathological mechanism. OBJECTIVE: The single-cell RNA-seq datasets of PCOS (GSE168404 and GSE193123) and RSA GSE113790 and GSE178535) were downloaded from the Gene Expression Omnibus (GEO) database. METHODS: Datasets of PSCO and RSA patients were retrieved from the Gene Expression Omnibus (GEO) database. The "WGCNA" package was used to determine the module eigengenes associated with the PCOS and RSA phenotypes and the gene functions were analyzed using the "DAVID" database. The GSEA analysis was performed in "clusterProfiler" package, and key genes in the activated pathways were identified using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Real-time quantitative PCR (RT-qPCR) was conducted to determine the mRNA level. Cell viability and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry, respectively. RESULTS: The modules related to PCOS and RSA were sectioned by weighted gene co-expression network analysis (WGCNA) and positive correlation modules of PCOS and RSA were all enriched in angiogenesis and Wnt pathways. The GSEA further revealed that these biological processes of angiogenesis, Wnt and regulation of cell cycle were significantly positively correlated with the PCOS and RSA phenotypes. The intersection of the positive correlation modules of PCOS and RSA contained 80 key genes, which were mainly enriched in kinase-related signal pathways and were significant high-expressed in the disease samples. Subsequently, visualization of these genes including PDGFC, GHR, PRLR and ITGA3 showed that these genes were associated with the PI3K-AKT signal pathway. Moreover, the experimental results showed that PRLR had a higher expression in KGN cells, and that knocking PRLR down suppressed cell viability and promoted apoptosis of KGN cells. CONCLUSION: This study revealed the common pathological mechanisms between PCOS and RSA and explored the role of the PI3K-AKT signaling pathway in the two diseases, providing a new direction for the clinical treatment of PCOS and RSA.

Humans↗
PubMed2004

Compound heterozygosity for Pten and SHIP augments T-dependent humoral immune responses and cytokine production by CD(4+) T cells.

Tight regulation of the phosphatidylinositiol 3-kinase (PI3K) pathway is essential not only for normal immune system development and responsiveness, but also in the prevention of immunopathology. Indeed, unchecked activation of the PI3K pathway in T cells induces lymphoproliferation and systemic autoimmunity. Evaluating the importance of threshold levels of two key PI3K pathway phosphoinositol phosphatases, we previously reported that mice heterozygous for both Pten and SHIP develop a more rapid progression of a lymphoproliferative autoimmune syndrome than do Pten(+\-) mice. Investigating the basis for this difference, we now describe a quantitative and qualitative difference in the antibody responses of C57BL\6 Pten(+\-) SHIP(+\-) mice upon challenge with a T-dependent antigen. Suspecting that this phenotypic difference might be the result, at least in part, of a T-helper cell defect, an in vitro analysis of anti-CD3/interleukin (IL)-2-expanded CD4(+) T cells was performed. After stimulation with anti-CD3, cells from mice heterozygous for both Pten and SHIP exhibited a striking increase in IL-4 secretion (> 10-fold), without a corresponding increase in T helper 2 (Th2) cell numbers being evident by intracellular staining for this cytokine. Modest increases were also seen for both IL-13 and IFN-gamma. Perhaps in keeping with this abnormal in vitro cytokine profile, IgG1 serum levels were significantly elevated in young C57BL\6 Pten(+\-) SHIP(+\-) mice. Thus, the relative levels of Pten and SHIP appear to be key variables in CD4(+) T-cell function, primarily via their ability to regulate IL-4 production.

Animals↗
PubMed2006

Control of mammalian oocyte growth and early follicular development by the oocyte PI3 kinase pathway: new roles for an old timer.

A large amount of information has accumulated over the past decade on how gonadotropins, steroid hormones and growth factors regulate development of the mammalian ovarian follicle. Moreover, the bi-directional communication between mammalian oocytes and their surrounding somatic (granulosa) cells has also been shown to be crucial for this process. The intra-ovarian factors, or more specifically, the intra-oocyte signaling pathways that control oocyte growth and early follicular development are largely unknown, however. Based on both in vitro studies and in vivo functional studies using gene-modified mouse models, this review focuses on the key features of the phosphatidylinositol 3 kinase (PI3K) pathway in growing mouse oocytes and on the novel functions of the oocyte PI3K pathway in controlling mammalian oocyte growth and follicular development that have come to light only recently. We propose that the PI3K pathway in the oocyte, which is activated by granulosa cell-produced Kit ligand (KL) via the oocyte-surface receptor Kit, may serve as an intra-oocyte network that regulates both oocyte growth and the early development of ovarian follicles.

Animals↗
PubMed2005

Insulin-like growth factor-I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal-regulated protein kinase and phosphatidylinositol 3-kinase pathways.

Vascular calcification develops within atherosclerotic lesions and results from a process similar to osteogenesis. One of the paracrine regulators of bone-derived osteoblasts, insulin-like growth factor-I (IGF-I), is also present in atherosclerotic lesions. To evaluate its possible role in vascular calcification, we assessed its in vitro effects on proliferation and differentiation in calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells. Results showed that IGF-I inhibited spontaneous CVC differentiation and mineralization as evidenced by decreased alkaline phosphatase (AP) activity and decreased matrix calcium incorporation, respectively. Furthermore, IGF-I inhibited the AP activity induced by bacterial lipopolysaccharide, TNF-alpha, or H2O2. It also induced CVC proliferation based on 3H-thymidine incorporation. Results from Northern analysis and tests using IGF-I analogs suggest that IGF-I effects are mediated through the IGF-I receptor. IGF-I also activated both the extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibition of either the ERK or PI3K pathway reversed IGF-I effects on CVC proliferation and AP activity, suggesting a common downstream target. Overexpression of ERK activator also mimicked IGF-I inhibition of lipopolysaccharide-induced AP activity. These results suggest that IGF-I promotes proliferation and inhibits osteoblastic differentiation and mineralization of vascular cells via both ERK and PI3K pathways.

Alkaline Phosphatase↗
PubMed2005

Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways.

Connexins (Cxs) provide a means for intercellular communication and play important roles in the pathophysiology of vascular cardiac diseases. Infection of endothelial cells (ECs) with first-generation E1/E3-deleted E4+ adenovirus (AdE4+) selectively modulates the survival and angiogenic potential of ECs by as of yet unrecognized mechanisms. We show here that AdE4+ vectors potentiate Cx expression in ECs in vitro and in mouse heart tissue. Infection of ECs with AdE4+, but not AdE4-, resulted in a time- and dose-dependent induction of junctional Cx40 expression and suppression of Cx43 protein and mRNA expression. Treatment of ECs with PKA inhibitor H89 or PI3K inhibitor LY294002 prevented the AdE4+-mediated regulation of Cx40 and Cx43 that was associated with diminished AdE4+-mediated survival of ECs. Moreover, both PKA activity and cAMP-response element (CRE)-binding activity were enhanced by treatment of ECs with AdE4+. However, there is no causal evidence of a cross-talk between the 2 modulatory pathways, PKA and PI3K. Remarkably, Cx40 immunostaining was markedly increased and Cx43 was decreased in the heart tissue of mice treated with intra-tracheal AdE4+. Taken together, these results suggest that AdE4+ may play an important role in the regulation of Cx expression in ECs, and that these effects are mediated by both the PKA/CREB and PI3K signaling pathways.

Adenoviridae↗
PubMed2001

Role of phosphatidylinositol 3-kinase in anti-IgM- and anti-IgD-induced apoptosis in B cell lymphomas.

Cross-linking of surface Ig receptors with anti IgM (anti-mu heavy chain, anti-mu), but not anti-IgD (anti-delta heavy chain, anti-delta), Abs leads to growth arrest and apoptosis in several extensively characterized B cell lymphomas. By poorly understood mechanisms, both Igs transiently stimulate c-Myc protein expression. However, ultimately, only anti-mu causes a severe loss in c-Myc and a large induction of p27(Kip1) protein expression. Because phosphatidylinositol 3-kinase (PI3K) has been established as a major modulator of cellular growth and survival, we investigated its role in mediating anti-Ig-stimulated outcomes. Herein, we show that PI3K pathways regulate cell cycle progression and apoptosis in the ECH408 B cell lymphoma. Anti-mu and anti-delta driven c-Myc protein changes precisely follow their effects on the PI3K effector, p70(S6K). Upstream of p70(S6K), signaling through both Ig receptors depresses PI3K pathway phospholipids below control with time, which is followed by p27(Kip1) induction. Conversely, anti-delta, but not anti-mu stimulated PI3K-dependent phospholipid return to control levels by 4-8 h. Abrogation of the PI3K pathway with specific inhibitors mimics anti-mu action, potentiates anti-mu-induced cell death and, importantly, converts anti-delta to a death signal. Transfection with active PI3K kinase construct induces anti-mu resistance, whereas transfection with dominant negative PI3K augments anti-mu sensitivity. Our results show that prolonged disengagement of PI3K or down-regulation of its products by anti-mu (and not anti-delta) determines B cell fate.

Animals↗
PubMed2005

Mutational and immunohistochemical analysis of ezrin-, radixin-, moesin (ERM) molecules in epilepsy-associated glioneuronal lesions.

Glioneuronal lesions are frequently observed in biopsy specimens obtained from patients with pharmacoresistant epilepsies, comprising focal cortical dysplasias (FCD) and gangliogliomas. Recent findings point to the phosphoinositide 3-kinase (PI3K) pathway and tuberin/hamartin signaling cascade as being compromised in these lesions. Ezrin, radixin and moesin (ERM-/band-4.1 proteins) genes represent downstream effectors of the PI3K pathway, are involved in cytoskeleton-membrane interference, cell growth, migration and differentiation, and harbor tumor suppressor motifs. Accumulation of band-4.1 proteins has been identified in cortical tubers of tuberous sclerosis patients, which share neuropathological similarities with FCD and gangliogliomas. Here, we have studied the immunohistochemical distribution pattern of ERMs, as well as allelic variants, occurring in gangliogliomas (n=20) and FCDs (FCD(IIa), n=7; FCD(IIb), n=37). Aberrant accumulation of ERMs was observed in dysplastic neurons of FCDs and gangliogliomas as well as in balloon cells. Adjacent brain tissue without structural abnormalities was used as control and showed only faint neuropil staining. Mutational screening revealed silent polymorphisms in the ezrin gene in two individuals suffering from FCD(IIb). A transition from G to A in radixin exon 2 resulted in an exchange of valine by isoleucine at codon 50 in an additional FCD(IIb) specimen. Such sequence alterations were not found in controls. The present data suggest accumulation of ERM expression in dysplastic cellular components but do not favor mutational events of ERM in the pathogenesis of FCDs or gangliogliomas. Aberrant expression of ERMs is, however, compatible with compromised PI3K-pathway signaling in glioneuronal lesions characterized by abnormal cellular differentiation and aberrant network formation.

Brain Diseases↗
PubMed2002

A PI3-kinase signaling code for insulin-triggered insertion of glucose transporters into the plasma membrane.

Activation of phosphatidyl-inositol-3'-OH-kinase (PI3K) and the resulting production of phosphatidyl-inositol-3,4,5-trisphosphate (PIP3) are ubiquitous signaling steps that link various cell surface receptors to multiple intracellular targets. In fat and muscle cells, the same PI3K pathway that regulates metabolic enzymes, proliferation, and differentiation has also been shown to be involved in insulin-triggered insertion of glucose transporter GLUT4 into the plasma membrane. The multiple PI3K functions raise the question of how the same PI3K pathway can be selectively used for different cell functions. Here we developed a dual-color evanescent wave microscopy method to simultaneously measure PIP3 production and GLUT4 insertion in individual 3T3L1 adipocytes. Activation of PI3K was found to be both necessary and sufficient for triggering GLUT4 insertion, but transporter insertion was markedly suppressed for small-amplitude, persistent PIP3 signals and for large-amplitude, short PIP3 signals. The rejection of these common PI3K signaling responses may explain the selective advantage of insulin over platelet-derived growth factor and other stimuli for inducing GLUT4 insertion. Our study suggests that the same PI3K pathway can control specific cell functions by relying on effector systems that respond to particular receptor-encoded time courses and amplitudes of PIP3 signals.

Cell Membrane↗
PubMed2006

Reelin induces the detachment of postnatal subventricular zone cells and the expression of the Egr-1 through Erk1/2 activation.

Reelin binds to very low-density lipoprotein receptor and apolipoprotein E receptor 2, thereby inducing mDab1 phosphorylation and activation of the phosphatidylinositide 3 kinase (PI3K) pathway. Here we demonstrate that Reelin activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway, which leads to the phosphorylation of Erk1/2 proteins. The inhibition of Src family kinases (SFK) blocked Reelin-dependent Erk1/2 activation. This was also shown in neuronal cultures from mDab1-deficient mice. Although rat sarcoma viral oncogene was weakly activated upon Reelin treatment, pharmacological inhibition of the PI3K pathway blocked Reelin-dependent ERK activation, which indicates cross talk between the ERK and PI3K pathways. We show that blockade of the ERK pathway does not prevent the chain migration of neurons from the subventricular zone (SVZ) but does inhibit the Reelin-dependent detachment of migrating neurons. We also show that Reelin induces the transcription of the early growth response 1 transcription factor. Our findings demonstrate that Reelin triggers ERK signaling in an SFK/mDab1- and PI3K-dependent manner and that ERK activation is required for Reelin-dependent transcriptional activation and the detachment of neurons migrating from the SVZ.

Animals↗
PubMed2004

Activation of PI3K-Akt pathway mediates antiapoptotic effects of beta-adrenergic agonist in airway eosinophils.

beta-Adrenoceptor agonists reportedly decrease spontaneous apoptosis of peripheral blood eosinophils; however, its signaling pathway is unknown. Survival signals can be elicited by the activation of phosphatidylinositol 3-kinase (PI3K) and Akt, both of which are known to be potent regulators of apoptosis, and Akt in turn inactivates Forkhead transcription factors, including FKHR (Forkhead in rhabdomyosarcoma). We have investigated the effect of beta-agonists on apoptosis of local eosinophils isolated from the airways and the involvement of PI3K, Akt, and FKHR in its survival signal. Eosinophils obtained from immunized mice by bronchoalveolar lavage after allergen provocation underwent apoptosis in a time-dependent manner. Incubation of eosinophils with isoproterenol or formoterol dose-dependently inhibited both spontaneous eosinophil apoptosis and apoptosis induced by Fas receptor activation. Incubation with cAMP or forskolin also inhibited eosinophil apoptosis. The PI3K inhibitors wortmannin and LY-294002 and an Akt inhibitor, 1-L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, but not a mitogen-activated protein kinase kinase inhibitor PD-98059, blocked isoproterenol-mediated eosinophil survival. Wortmannin also inhibited cAMP-mediated eosinophil survival. Isoproterenol rapidly induced phosphorylation of Akt and FKHR in eosinophils in a PI3K-dependent manner. These findings indicate that the PI3K-Akt-FKHR pathway conveys a critical survival signal induced by beta-agonists in airway eosinophils.

Adrenergic beta-Agonists↗
PubMed2005

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of multiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of multiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.

Apoptosis↗
PubMed2006

Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation.

Uterine cervical carcinogenesis is probably dependent on cellular genetic damage in addition to the integration of high-risk HPV DNA in the epithelial cell genome. Gain of chromosome 3q24-29 is commonly observed in cervical neoplasia. The putative oncogene PIK3CA located in this region encodes a phosphatidylinositol 3-kinase (PI3K). In a process reversed by PTEN, PI3K generates inositol phospholipids that trigger AKT phosphorylation, which in turn effects tumor driving signals. We studied 46 specimens of formalin-fixed, paraffin-embedded cervical neoplastic tissue. The activation state of the PI3K-AKT pathway was assessed immunohistochemically using an antibody with specificity towards serine 473-phosphorylated AKT. AKT phosphorylation was found in 39 out of 46 examined specimens. To examine the possible molecular basis for this activation, we searched for PIK3CA amplification using quantitative real-time polymerase chain reaction. PIK3CA gene copy number was estimated to be 3 or more in 28 out of 40 successfully examined cases. Further, a PTEN mutation analysis of all 9 PTEN exons was carried out, but except for 1 metastasis with an exon 9 V369I heterozygosity, all cases showed normal PTEN sequence. Immunohistochemical staining for PTEN was strong in all lesions. In conclusion, an increased activation state of AKT kinase appears to be present in cervical carcinogenesis, and may be accounted for by PIK3CA amplification, whereas PTEN mutation seems to be of little importance.

Carcinoma, Squamous Cell↗
PubMedDate not supplied

CD151 gene delivery activates PI3K/Akt pathway and promotes neovascularization after myocardial infarction in rats.

Our previous study showed that CD151 promotes neovascularization and improves blood perfusion in a rat hindlimb ischemia model. In this study, we investigated whether CD151 promotes neovascularization and improves ventricular function after myocardial infarction in rats and the mechanisms involved. Rats were subjected to sham surgery or coronary artery ligation. We used rAAV for direct delivery of the human CD151 gene into the rat myocardium. At 4 weeks after coronary artery ligation, human CD151 mRNA was detected using RT-PCR. Measurement of capillary density was evaluated using immunostaining for von Willebrand factor, and hemodynamic variables and physiological parameters were monitored. Western blot analysis for CD151, PI3K, phosphor-Akt, total Akt, phosphor-eNOS, and total eNOS was performed. In addition, we also observed the effect of CD151 on the expression of VEGF using Western blot analysis. CD151 gene delivery could increase the expression of CD151 at gene and protein levels. Overexpression of CD151 could increase the number of microvessels in the ischemic myocardium and significantly improved the hemodynamic variables after myocardial infarction. In addition, CD151 could activate the PI3K pathway, including activation of Akt and eNOS, but did not affect the expression of VEGF. This study suggested that CD151 could promote neovascularization and improve ventricular function after myocardial infarction in rats. The mechanism may be that CD151 can activate the PI3K pathway and promote neovascularization via the PI3K pathway, without affecting ischemia-induced VEGF expression.

Animals↗
PubMed2004

Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer.

PURPOSE: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited. EXPERIMENTAL DESIGN: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples. RESULTS AND CONCLUSIONS: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer.

Antibodies, Monoclonal↗
PubMed2001

Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway.

The PI3K-Akt signaling pathway plays a critical role in mediating survival signals in a wide range of neuronal cell types. The recent identification of a number of substrates for the serine/threonine kinase Akt suggests that it blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, recent experiments suggest that Akt may also use metabolic pathways to regulate cell survival.

Animals↗