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PubMed2003

[Direct involvement of the supraspinal phosphoinositide 3-kinase/phospholipase C gamma 1 pathway in the mu-opioid receptor agonist-induced supraspinal antinociception in the mouse].

Recent works have documented that the stimulation of the mu-opioid receptor (MOR) can activate phosphoinositide-specific phospholipase C (PI-PLC). Here I demonstrate that PLC beta 3 isoform activated by beta gamma subunit of G-protein (G beta gamma) in the brain may contribute to the negative modulation for supraspinal antinociception induced by morphine in mice. In immunohistochemical studies, phosphoinositide 3-kinase (PI3K) was detected in the membrane of the cell soma and the immunoreactivity of PI3K (PI3K-IR) was almost overlapped with MOR-IR and PLC gamma 1-IR in the periaqueductal gray matter (PAG) that is considered to be one of the most important sites for the expression of MOR-mediated antinociception. Morphine produced a marked increase in the protein level of membrane-bound PLC gamma 1, and this increase induced by morphine was significantly inhibited by intracerebroventricullar (i.c.v.) pretreatment with PI3K inhibitors at the dosage that suppressed the morphine-induced supraspinal antinociception. Furthermore, morphine also caused a robust increase in the number of phosphorylated-PLC gamma 1 (p-PLC gamma 1) expressing cells in the PAG. It is worthwhile to note that MOR-IR was overlapped with p-PLC gamma 1-IR in the same cells that also contained PI3K in this region. Based on these findings, the next experiment was designed to investigate whether a deletion of the PLC gamma 1 gene by i.c.v. pretreatment with antisense oligodeoxynucleotide (AS-ODN) against PLC gamma 1 could affect the antinociception induced by MOR agonists. Pretreatment with AS-ODN against PLC gamma 1 revealed a significant inhibition of supraspinal antinociception induced by MOR-agonists. In addition, the morphine-induced supraspinal antinociception was suppressed by the blockade of the G beta gamma subunit that can directly activate both PI3K and PLC gamma 1. Moreover, mice lacking the gene for inositol 1,4,5-trisphosphate (IP3)-sensitive receptors, which can modulate the release of Ca2+ from the endoplasmic reticulum, exhibited a significant inhibition of the morphine-induced antinociception. Collectively, these findings raise the possibility that the activation of the PLC pathway associated with the stimulation of PI3K and/or G beta gamma is implicated in supraspinal antinociception induced by MOR agonists in mice.

Analgesics, Opioid↗
PubMed2003

Phosphoinositide 3-kinase cascade facilitates mu-opioid desensitization in sensory neurons by altering G-protein-effector interactions.

Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. Here we investigated the role of phosphoinositide 3-kinase (PI3K) and its downstream pathways in desensitization of micro-opioid inhibition of neuronal Ca2+ channels. In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the micro agonist [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin (DAMGO). Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). A combined application of PI3K and MAPK inhibitors showed no additive effect, suggesting that these two kinases act in a common pathway to facilitate chronic desensitization. Acute DAMGO desensitization, however, was not affected by the inhibitors. Furthermore, upregulation of the PI3K-Akt pathway in mutant mice lacking phosphatase and tensin homolog, a lipid phosphatase counteracting PI3K, selectively enhanced chronic desensitization in a PI3K- and MAPK-dependent manner. Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between betagamma subunits of G-proteins and Ca2+ channels. DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. Such disruption could occur at the postreceptor level, because chronic DAMGO also reduced GTPgammaS-induced PPF that was independent of receptor activation. Again, inhibition of PI3K or MAPK reduced desensitization of PPF. Our data suggest that the PI3Kcascade involving MAPK and Akt enhances micro-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions.

Animals↗
PubMed2004

Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue factor and thrombomodulin expression.

BACKGROUND AND OBJECTIVES: Retinoids are involved in cell differentiation, morphogenesis, proliferation and antineoplasic processes. Thus, the retonoic acid receptor (RARalpha) agonist, AM80, regulates tissue factor (TF), thrombomodulin (TM) expression and granulocytic differentiation in promyelocytic cells, while the RARgamma-selective retinoid, CD437, inhibits in vitro cell proliferation and induces apoptosis. The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K) pathways constitute key integration points along the signal transduction cascades that link diverse extracellular stimuli to proliferation, differentiation and survival. DESIGN AND METHODS: PI3K and MEK/ERK kinase-dependent pathways were examined as potential targets of retinoid signaling. Likewise, by using specific inhibitors, the role of those kinases in retinoid-induced granulocytic differentiation, apoptosis, and TF and TM expression n NB4 cells were analyzed. RESULTS: AM80-treated NB4 cells had increased PI3K activity and phosphoinositide turnover. High steady-state pERK-1/-2 activity levels were not significantly changed by AM80. Yet, PI3K inhibitor LY294002 significantly reduced AM80-elicted ERK-1/-2 activity. Thus, the PI3K pathway might contribute to elevated ERK-1/-2 activity in NB4 cells. Inhibition of the PI3K and MEK/ERK pathways reversed AM80-induced granulocytic differentiation, TF down-regulation and TM induction. Besides, CD437 significantly reduced ERK-1/-2 activity of NB4 cells. Further ERK-1/-2 activity inhibition with the MEK inhibitor, PD98059, increased the retinoid pro-apoptotic effect with an additive effect. INTERPRETATION AND CONCLUSIONS: Regardless the different regulation of PI3K and MAPK pathways promoted by AM80 and CD437, there is a varying degree of cross-talk between these pathways in the control of the overall response of promyelocytic cells to retinoids. Thus, disruption of targeted pathways, together with specific retinoids, might be an effective therapeutic treatment for acute promyelocytic leukemia.

Apoptosis↗
PubMed1996

Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11.

Tyrosine phosphorylation is an early event of interleukin-11 (IL-11)-mediated signal transduction. The IL-11-responsive cell line 3T3-L1 (mouse preadipocytes) was tested for the presence of Src-family protein tyrosine kinases (PTKs). Only p62yes, p59fyn, and p60src were found to be expressed. Immune-complex kinase reactions using the artificial substrate enolase showed that upon stimulation with IL-11, p62yes and p60src were activated, but p59fyn did not appear to be activated. These results correlate with antiphosphotyrosine (APT) immunoblots. IL-11-stimulated cells also revealed increased phosphatidylinositol 3-kinase (PI3K) activity. Increased activity of PI3K was found to be associated with tyrosine phosphorylated proteins and p62yes, after IL-11 treatment. Immunoprecipitation studies with anti-PI3K revealed for the first time that p62yes associated with PI3K in response to IL-11. To summarize, IL-11 activates p60src, p62yes and PI3K but not p59fyn, and this activation of p62yes leads to its association with PI3K and PI3K activation.

3T3 Cells↗
PubMed1998

Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5.

Activation and recruitment of eosinophils in allergic inflammation is in part mediated by chemoattractants and T-helper 2 (Th2)-derived cytokines. However, little is known concerning the signal transduction mechanisms by which this activation occurs. We have investigated tyrosine kinase-mediated activation of phosphatidylinositol 3-kinase (PI3K) and compared this with the activation of the p21ras-ERK signaling pathway in human eosinophils. The related cytokines interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF), all induced PI3K activity detected in antiphosphotyrosine immunoprecipitates. Furthermore, the chemoattractants platelet-activating factor (PAF), RANTES, and C5a were also able to induce phosphotyrosine-associated PI3K activity. Protein kinase B (PKB) is a downstream target of PI3K activation by growth factors. Induction of PKB phosphorylation in human eosinophils was transiently induced on activation with the cytokines IL-4 and IL-5, as well as the chemoattractants PAF, C5a, and RANTES showing a broad activation profile. Surprisingly, analysis of the activation of the mitogen-activated protein (MAP) kinases p44(ERK1) and p42(ERK2), showed that ERK2, but not ERK1, was transiently activated in human eosinophils after stimulation with IL-5 or PAF. Activation kinetics correlated with activation of p21ras by both cytokines and chemoattractants as measured by a novel assay for guanosine triphosphate (GTP)-loading. Finally, using specific inhibitors of both the p21ras-ERK and PI3K signaling pathways, a role was demonstrated for PI3K, but not p21ras-ERK, in activation of the serum-treated zymosan (STZ)-mediated respiratory burst in IL-5 and PAF-primed eosinophils. In summary, these data show that in human eosinophils, Th2-derived cytokines differentially activate both PI3K and MAP kinase signal transduction pathways with distinct functional consequences showing complex regulation of eosinophil effector functions.

Cells, Cultured↗
PubMed1998

Activation of the c-fos serum response element by phosphatidyl inositol 3-kinase and rho pathways in HeLa cells.

Many growth factors rapidly induce transcription of the c-fos proto-oncogene. We have investigated the pathways for induction of the c-fos promoter by serum and epidermal growth factor (EGF) in HeLa cells. Induction of the serum response element (SRE) of the c-fos promoter could be split into two parts, one involving the serum response factor-associated ternary complex factor (TCF) factors and the second mediated by core SRE sequences. Serum induction was mediated primarily by the core SRE, whereas EGF used both the TCF and core SRE pathways. Using activated and inhibitory signaling proteins, we found that phosphatidyl inositol 3-kinase (PI3K) and rho family members could mediate activation by serum. Activation by PI3K was mediated by core SRE sequences and was dependent upon rac and rho, suggesting a PI3K-to-rac-to-rho pathway for core SRE activation. The PI3K target Akt was also capable of activating the SRE but functioned through the TCF pathway, suggesting that Akt does not mediate the primary PI3K pathway to the SRE and that Akt is capable of activating TCF family members. Serum and EGF induction of the core SRE was partially inhibited by rho and PI3K inhibitors. The use of these inhibitors demonstrates the complexity of signaling pathways to the SRE and suggests that serum activates rho by PI3K-dependent and -independent pathways.

3T3 Cells↗
PubMed1999

Enhancement of chemotactic peptide-induced activation of phosphoinositide 3-kinase by granulocyte-macrophage colony-stimulating factor and its relation to the cytokine-mediated priming of neutrophil superoxide-anion production.

Incubation of human neutrophils with a chemotactic peptide [N-formylmethionyl-leucylphenylalanine (fMLP)] gave rise to an increase in the phosphoinositide 3-kinase (PI3K) activity, phosphorylation of p47phox and superoxide-anion (O2(-)) generation in the same fMLP-concentration-dependent manner. These responses to fMLP were markedly enhanced when the cells had been incubated for 10 min before the addition of fMLP with increasing concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) that were only slightly effective themselves. Wortmannin, an inhibitor of PI3K, suppressed all of these fMLP actions in the same concentration-dependent manner in either GM-CSF-primed or non-primed cells. Sustained activation of protein kinase C by the addition of PMA caused marked phosphorylation of p47phox and respiratory burst itself without activation of PI3K. This strong action of PMA was not primed by GM-CSF. The chemotactic peptide was without effect in pertussis-toxin-treated cells, indicating that its actions are mediated by betagamma-subunits liberated from toxin-susceptible heterotrimeric Gi proteins (Gbetagamma). Thus one of the mechanisms of GM-CSF-mediated priming of fMLP-induced respiratory burst is synergistic activation of wortmannin-sensitive PI3K by Gbetagamma in the presence of tyrosine-phosphorylated proteins in GM-CSF-treated cells, as recently indicated in a cell-free system [Kurosu, Maehama, Okada, Yamamoto, Hoshino, Fukui, Ui, Hazeki and Katada (1997) J. Biol. Chem. 272, 24252-24256]. GM-CSF primed fMLP-induced MAP (mitogen-activated protein) kinase activation enormously as well. The MAP kinase activation was primed even in the presence of wortmannin, indicating that PI3K was not the sole site where tyrosine kinase-related and Gbetagamma-mediated intracellular signals converge to elicit the priming. The GM-CSF priming of fMLP-induced PI3K activation and O2(-) generation was much smaller in magnitude in neutrophils in which cAMP accumulated upon incubation with prostaglandin E1 than in the cells without the nucleotide accumulation. Thus the GM-CSF priming site, in addition to PI3K, might be just the target of cAMP-dependent protein kinase A in fMLP-initiated signalling cascades or could be localized immediately downstream thereof.

Androstadienes↗
PubMed2026

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability.

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

PI3K signaling↗
PubMed2004

Frontline: The p85alpha isoform of phosphoinositide 3-kinase is essential for a subset of B cell receptor-initiated signaling responses.

Phosphoinositide 3-kinase (PI3K) is a ubiquitously expressed signaling enzyme that plays an integral role in development and activation of B cells. B cell receptor (BCR)-driven proliferation is completely blocked either in cells lacking the p85alpha regulatory isoform of PI3K or in wild-type cells treated with pharmacological PI3K inhibitors. However, the contribution of p85alpha to early signaling events has not been fully investigated. Here we show that B cells lacking p85alpha have signaling impairments that are both quantitatively and qualitatively different from those in cells treated with PI3K inhibitors. Loss of p85alpha results in partial reductions in Ca2+ mobilization and IkappaB phosphorylation, whereas ERK phosphorylation is not diminished. Moreover, although Akt phosphorylation is partially reduced, phosphorylation of several proteins downstream of Akt is preserved. These partial impairments suggest that there are other routes to PI3K activation in B cells apart from p85alpha-associated catalytic subunits. Notably, addition of phorbol ester restores BCR-mediated proliferation in p85alpha-deficient cells but not wild-type cells treated with PI3K inhibitors. These findings suggest that the primary BCR signaling defect in B cells lacking p85alpha is a failure to activate diacylglycerol-regulated signaling enzymes, most likely protein kinase C.

Animals↗
PubMed2004

Commentary: New insights into the complexity of phosphatidylinositol lipid signaling in B lymphocytes.

Stimulation of B cells through the B cell antigen receptor (BCR) leads to the activation of numerous intracellular signaling pathways including phosphoinositide (PI) 3-kinases (PI3K). These generate the 3-PI lipids which in turn act as critical second messengers. Gene-targeting experiments had shown that B cells deficient in p85alpha, an adaptor protein required for PI3K function, were defective in their ability to proliferate in response to BCR stimulation. In this issue of the European Journal of Immunology, Hess et al. report analysis of intracellular signaling pathways in p85alpha-deficient B cells and show that in the absence of p85alpha there is a partial impairment in BCR-induced calcium flux, and a reduction in activation of the transcription factor NF-kappaB. Unexpectedly, they show that while the BCR-induced phosphorylation of the PI3K-dependent kinase Akt is reduced in p85alpha-deficient cells, the phosphorylation of two downstream targets of Akt -- FOXO1 and ribosomal protein S6 -- is largely unaffected. Furthermore, they show that treatment of wild-type B cells with PI3K inhibitors had a more profound effect than disruption of the p85alpha gene. Taken together, these results indicate that in the absence of p85alpha, there is still significant residual PI3K activity. These results highlight the need for careful measurement of PI3K activity in gene-targeted mice and cells, by directly measuring levels of the 3-PI lipids.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases.

Class I phosphoinositide 3-kinases (PI3K) are known to play a significant role in neutrophil chemotaxis. However, the relative contributions of different PI3K isoforms, and how these impact on lung inflammation, have not been addressed. In vitro studies using wild-type and PI3Kgamma knockout neutrophils demonstrated the major role of the gamma isoform in chemotactic but not chemokinetic events. This was confirmed by a model of direct chemokine instillation into the airways in vivo. Within all studies, a low yet significant degree of neutrophil movement in the absence of PI3Kgamma could be observed. No role for the delta isoform was demonstrated both in vitro and in vivo using PI3Kdelta kinase-dead knock-in mice. Moreover, further studies using the broad-spectrum PI3K inhibitors wortmannin or LY294002 showed no other class I PI3K isoforms to be involved in these chemotactic processes. Here, we identify a contributory PI3K-independent mechanism of neutrophil movement, yet demonstrate PI3Kgamma as the pivotal mediator through which the majority of neutrophils migrate into the lung in response to chemokines. These data resolve the complexities of chemokine-induced neutrophilia and PI3K signaling and define the gamma isoform as a promising target for new therapeutics to treat airway inflammatory diseases.

Animals↗
PubMed2003

GDNF and insulin cooperate to enhance the proliferation and differentiation of enteric crest-derived cells.

Previously we have shown that glial derived neurotrophic factor (GDNF) stimulates modest increases in the proliferation of avian enteric crest-derived cells and similar increases in the phosphorylation of the phosphoinositide 3-kinase (PI3K) downstream substrate Akt (Akt-P). In the present study we tested whether GDNF-independent increases in PI3K activation would be sufficient to support proliferation. We found that insulin induces a large increase in the phosphorylation of Akt and can initiate DNA synthesis in avian enteric crest-derived cells, but is unable to maintain proliferation over time in culture, measured by BrdU incorporation. GDNF can also initiate DNA synthesis, but it too is unable to maintain BrdU incorporation in cultured enteric crest-derived cells. Sustained incorporation of BrdU after 16-48 h in culture is shown to be dependent on a combination of GDNF and insulin. Using a phospho-specific antibody, we found Akt-P levels to be similar in the proliferating (BrdU incorporation maintained from 16-48 h in culture) and nonproliferating populations, suggesting that Akt-P levels were not solely controlling the extent of BrdU incorporation. A minimum level of PI3K activation, however, is required, as shown by the dose-dependent reduction in proliferation with the PI3K inhibitor LY-294002. We conclude that the integrity of the PI3K pathway is essential for enteric crest-derived cell proliferation, but that the absolute levels of Akt-P do not determine the extent of proliferation. The enhanced proliferation in cultures containing both GDNF and insulin suggests that other pathways are involved, including the possibility that PI3K downstream effectors other than Akt are important in the regulation of avian enteric crest-derived cell proliferation.

Animals↗
PubMed1994

Role of phosphatidylinositol-3-kinase in insulin receptor signaling: studies with inhibitor, LY294002.

In order to study the role of phosphatidylinositol-3-kinase (PI3K) in insulin action, we employed a specific inhibitor of PI3K, LY294002, and measured five biological functions of insulin in mouse 3T3 fibroblasts overexpressing human insulin receptors. LY294002 had no effect on tyrosine phosphorylation of both the insulin receptor beta-subunit and insulin receptor substrate 1 (IRS-1) and did not influence the association of the p85 subunit of PI3K with IRS-1. However, LY294002 partially inhibited insulin stimulated glucose uptake, amino acid uptake and protein synthesis, while it completely inhibited insulin stimulation of DNA synthesis and p70 S6 kinase activation. These data suggest that: 1) PI3K plays a crucial role in various functions of insulin; and 2) there exist multiple signaling pathways (both PI3K dependent and PI3K independent) for the insulin receptor.

3T3 Cells↗
PubMed2002

Preferential binding of Grb2 or phosphatidylinositol 3-kinase to the met receptor has opposite effects on HGF-induced myoblast proliferation.

Hepatocyte growth factor (HGF) and its receptor, Met, play a crucial role in regulating adult skeletal myoblast proliferation and differentiation. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines, which act as docking sites for a number of intracellular mediators. These include Grb2 and p85, which couple the receptor with the Ras and phosphatidylinositol 3-kinase (PI3K) pathways, respectively. In this study, we define the role of these effectors in response to HGF by utilizing Met mutants, designed to obtain preferential coupling of Met to either Grb2 or PI3K or both. We found that relative to the wild-type receptor, enhanced binding to Grb2 further increases the incorporation of bromodeoxyuridine and the expression of Twist, while decreasing that of p27(Kip1) and myogenin. Conversely, preferential coupling with PI3K induced cell-cycle withdrawal and differentiation. Whereas enhanced Grb2 binding increased the phosphorylation of the mitogen-activated protein kinase/extracellular signal-regulated protein kinases (MAPK/ERK) and abrogated that of p38 MAPK, PI3K had the opposite effect. PD098059 reversed the inhibitory effects of Met on cell proliferation and differentiation, while wortmannin had only a very marginal effect. Taken together, these data suggest that coupling of Met with Grb2 is necessary for HGF-mediated inhibition of muscle differentiation. This inhibition occurs only when PI3K signaling downstream of Met is low. Imposing an efficient coupling of PI3K to Met would lead to upregulation of muscle regulatory factors and subsequent cell differentiation.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo.

BACKGROUND AND AIMS: Recently we demonstrated that phosphatidylinositol 3-kinase (PI3K) is overexpressed in human lung cancer. This study evaluated whether the PI3K inhibiting agent wortmannin affects proliferation of human lung cancer cells in vitro and in vivo. METHODS: Effects of exposure of human non-small-cell lung cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in vitro by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we examined the effects of blocking PI3K by wortmannin prior to xenotransplantation of human NSCLC cells into SCID-bg mice and the effect of systemic wortmannin administration following intrapulmonary xenotransplantation of human NSCLC. RESULTS: Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin inhibited proliferation in correlation to concentration in vitro. In vivo the blocking of PI3K by wortmannin prior to xenotransplantation caused a significant delay in the growth of subcutaneously induced tumors. Systemic wortmannin administration increased mean survival after intrapulmonary xenotransplantation of human NSCLC significantly by 38% and 47%. CONCLUSIONS: These data suggest inhibition of PI3K activity as a potential target for treatment of human NSCLC. Systemic toxicity of wortmannin requires development of improved PI3K inhibitors with favorable pharmacological properties.

Androstadienes↗
PubMed2005

PI3-kinase is essential for ADP-stimulated integrin alpha(IIb)beta3-mediated platelet calcium oscillation, implications for P2Y receptor pathways in integrin alpha(IIb)beta3-initiated signaling cross-talks.

Phosphatidylinositol 3-kinase (PI3K) pathway is important for platelet activation. Recent studies showed that PI3K and oscillative calcium could cross talk to each other and positively regulate integrin alpha (IIb)beta3-mediated outside-in signaling. However, the mechanism of this feedback regulation remains to be further characterized. Here we found that treatments of both PI3K inhibitor wortmannin and P2Y1 inhibitor A3P5P could inhibit granular secretion in platelets. Additionally, when RGD-substrate adherent platelets were treated with the ADP scavenger apyrase to deplete the granular-released ADP, their attachments in engaging with substrates became looser and the frequency of calcium oscillation decreased. Since it is known that ADP stimulates the PI3K and calcium signal primarily through P2Y12 and P2Y1 receptors respectively, our data indicated that integrin alpha(IIb)beta3 downstream PI3K and calcium activation might be not completely coupled to integrin associated signaling complex, but in part through feedback stimulation by granular released ADP. Our data indicates the important roles of PI3K and granular released ADP in coordinating the feedback regulations in integrin alpha(IIb)beta3-mediated platelet activation.

Actins↗
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↗
PubMed2004

Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling.

Phosphoinositide 3-kinase (PI3K) activation is essential for lymphocyte proliferation driven by receptors for antigen, costimulatory ligands and cytokines. The lipid products of PI3K contribute to the assembly of membrane-associated signaling complexes by promoting recruitment of selected proteins from the cytoplasm. Many proteins possess domains that are able to bind selectively to PI3K products. Different 'PI3K effector' proteins are coupled to distinct biological responses, depending on cell type and on the receptor that is engaged. In B cells and T cells, Tec-family tyrosine kinases and Akt serine/threonine kinases are emerging as crucial mediators of proliferation and survival signals downstream of PI3K. Of particular interest is recent evidence that PI3K signaling controls increases in lymphocyte size and metabolic activity that accompany cell cycle progression.

1-Phosphatidylinositol 4-Kinase↗