Murine D type cyclins associate with a catalytic subunit (p34PSK-J3) with properties distinct from known cyclin-dependent kinases (cdks). Mouse p34PSK-J3 shows less than 50% amino acid identity to p34cdc2, p33cdk2, and p36cdk3, lacks a PSTAIRE motif, and does not bind to p13suc1. Cyclin D1-p34PSK-J3 …

The phosphatidylinositol 3-kinase (PI3K) signalling pathway is one of the most frequently genetically altered pathways in human cancers (Samuels et al., 2004). Class I PI3Ks are lipid kinases that bind to the cell membrane and phosphorylate the lipid substrate, phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2), in order to produce the second messenger, PIP3. In turn, this regulates several biological signalling pathways involved in cell growth, proliferation, differentiation, and survival (Qiu et al., 1998; Roche, Koegl, & Courtneidge, 1994; Yao & Cooper, 1995). The work in this thesis explores how different PI(4,5)P2 fatty acyl chain arrangements and specific PI3K amino acids can affect membrane binding interactions and catalysis events for both wild-type (WT) and oncogenic class I PI3Ks. Firstly, the effects of different PI(4,5)P2 lipid species were investigated on PI3K lipid kinase activity using biochemical methods, and on PI3K membrane binding using biophysical methods. The influences of ...

TY - JOUR. T1 - Ras oncoprotein induces CD44 cleavage through phosphoinositide 3-OH kinase and the Rho family of small G proteins. AU - Kawano, Yoshiaki. AU - Okamoto, Isamu. AU - Murakami, Daizo. AU - Itoh, Hiroshi. AU - Yoshida, Masaki. AU - Ueda, Shoichi. AU - Saya, Hideyuki. PY - 2000/9/22. Y1 - 2000/9/22. N2 - CD44 is a cell surface adhesion molecule for several extracellular matrix components. We previously showed that CD44 expressed in cancer cells is proteolytically cleaved at the ectodomain through membrane-anchored metalloproteases and that CD44 cleavage plays a critical role in cancer cell migration. Therefore, cellular signals that promote the migration and metastatic activity of cancer cells may regulate the CD44 ectodomain cleavage. Here, we demonstrate that the expression of the dominant active mutant of Ha-Ras (Ha-RasVal-12) induces redistribution of CD44 to the newly generated membrane ruffling area and CD44 ectodomain cleavage. The migration assay revealed that the CD44 ...

[75 Pages Report] Check for Discount on Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Beta Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Beta or PIK3CB or EC 2.7.1.153) - Pipeline Review, H2 2017 report by Global Markets Direct. Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Beta Isoform (...

TY - JOUR. T1 - Protein kinase B (c-Akt). T2 - A multifunctional mediator of phosphatidylinositol 3-kinase activation. AU - Coffer, Paul J.. AU - Jin, Jing. AU - Woodgett, James R.. PY - 1998/10/1. Y1 - 1998/10/1. N2 - While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membrane-restricted second messenger, polyphosphatidylinositides containing a 3-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)/AKT and PtdIns(3,4,5)P3-dependent kinases 1 and 2, the first two of which interact with 3-phosphorylated phosphoinositides via pleckstrin ...

Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity. [provided by RefSeq, Jun 2016 ...

Lipid kinase activity of PI(3)K increased within 5 min of TNF stimulation and was maximal at 20 min. Probing Western blots of proteins from 293 cells with antibody to activated (phosphorylated) Akt revealed a temporal correlation with PI(3)K activity, an effect blocked by wortmannin. Dominant-negative PI(3)K transfection abrogated the 2.3-fold increase in Akt activity.. EMSA studies showed NF-?B activity in response to TNF stimulation and inhibition by wortmannin. Activity was enhanced by transient transfection with constitutively active PI(3)K or constitutively active Akt or NIK. Cotransfection of NIK with constitutively active Akt or PI(3)K produced an additive effect on NF-?B binding to DNA, while dominant negative PI(3)K inhibited NF-?B activation and dominant-negative NIK or wortmannin abrogated PI(3)K activation of NF-&?B. While constitutively active Akt alone promoted NF-?B binding to DNA, kinase-dead Akt inhibited it, showing Akt to be essential for NF-?B activation. However, ...

Beta-1 adrenergic receptor, Beta-2 adrenergic receptor, Beta-3 adrenergic receptor, Mitogen-activated protein kinase 1, Phosphatidylinositol 3-kinase regulatory subunit alpha, Phosphatidylinositol 3-kinase regulatory subunit beta, Phosphatidylinositol 3-kinase regulatory subunit gamma, CAMP ...

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InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.

Phosphoinositide 3-kinase (PI3K) type IA is a heterodimer of a catalytic subunit, p110, and a regulatory subunit, p85. Here we show that p85 contains a GTPase-responsive domain and an inhibitory domain, which together form a molecular switch that regulates PI3K. H-Ras and Rac1 activate PI3K by targe …

The phosphoinositide 3-kinase (PI3K) family catalyses the addition of a phosphate group to the D-3 position of polyphosphoinositides (PPIn). Since the discovery in the late 80s that...

Inositol 5-phosphatase, which converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate. Also converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate in vitro. May be involved in modulation of the function of inositol and phosphatidylinositol polyphosphate-binding proteins that are present at membranes ruffles (By similarity).

Mutations in the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K, encoded by PIK3CA) are common in breast cancer. Drugs inhibiting PI3K show efficacy in a small proportion of patients; some tumors are intrinsically resistant, whereas others become resistant. Le et al. found that another kinase, proviral insertion site in murine leukemia virus (PIM), maintains the activity of downstream effectors of the PI3K pathway and that cotargeting PIM may be effective in patients that show resistance to PI3K inhibitors. A large gain-of-function screen in cultured PI3K-mutant, luminal A-type breast cancer cells identified genes encoding isoforms of PIM as promoting resistance to the PI3K inhibitor BYL719. Overexpression of PIM1 (more so than that of PIM2 or PIM3) decreased the potency of BYL719 and other PI3K pathway inhibitors in various types of breast cancer cells. Cultures of PI3K-mutant breast cancer cells that were resistant to BYL719 had greater abundance of all three PIM isoforms than ...

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Regulatory subunit of the PI3K gamma complex. Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. Required for G protein-mediated activation of PIK3CG (By similarity).

The PDB archive contains information about experimentally-determined structures of proteins, nucleic acids, and complex assemblies. As a member of the wwPDB, the RCSB PDB curates and annotates PDB data according to agreed upon standards. The RCSB PDB also provides a variety of tools and resources. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists.

The PDB archive contains information about experimentally-determined structures of proteins, nucleic acids, and complex assemblies. As a member of the wwPDB, the RCSB PDB curates and annotates PDB data according to agreed upon standards. The RCSB PDB also provides a variety of tools and resources. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists.

TY - JOUR. T1 - Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. AU - Cheung, Lydia W T. AU - Walkiewicz, Katarzyna Wiktoria. AU - Besong, Tabot M.D.. AU - Guo, Huifang. AU - Hawke, David H.. AU - Arold, Stefan T.. AU - Mills, Gordon B.. N1 - KAUST Repository Item: Exported on 2020-10-01. PY - 2015/7/29. Y1 - 2015/7/29. N2 - The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α ...

Insulin-like growth factor-1 prevents Abeta[25-35]/(H2O2)- induced apoptosis in lymphocytes by reciprocal NF-kappaB activation and p53 inhibition via PI3K-dependent pathway ...

OriGene offers comprehensive product solutions for studying human protein kinases. Our functional kinome cDNA collection was featured in a Cell publication in 2008.

Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving their invasive capacity and metastatic potential. Therefore hRad50 the concentrations of PTX were set as 1 nM 2.5 nM and 5 nM for the subsequent experiments. In the morphological investigation the CCKS-1 cells changed into a spindle morphology and became separated by the administration … Read more Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving. Read More ...

Weve investigated the ability of anti-CD28 antibody costimulation to induce resistance to macrophage (M)-tropic strains of human immunodeficiency computer virus type 1 (HIV-1) in vitro. cells were passaged constantly on freshly coated plates. If the beads were removed after initial stimulation, p24 production increased over time and produced a result intermediate to the other forms … Read more Weve investigated the ability of anti-CD28 antibody costimulation to induce resistance. Read More ...

In contrast to what has been reported regarding PDGFR (Joly et al., 1994), our results indicate that the intracellular trafficking of EGFR does not require EGF‐stimulated PI3K activity. Among the three classes of PI3Ks, only class I p85/p110 PI3Ks are activated by EGFR and PDGFR (Hu et al., 1992; Rodriguez‐Viciana et al., 1994). To completely inhibit EGF‐stimulated PI3K activity, SKBR‐3 and 293T cells were transfected with the kinase‐deficient p110α subunit p110Δkin (Hu and Schlessinger, 1994). We showed that transfection of cells with p110Δkin had no effect on the EGF‐stimulated lysosomal targeting and degradation of EGFR (Figure 1). It has been reported that microinjection of inhibitory anti‐p110α antibodies did not block the transit of internalized PDGFR to perinuclear compartments (Siddhanta et al., 1998).. In addition, we showed that inhibition of PI3K activity by 100 nM or 20 μM LY294002 does not block the EGF‐induced lysosomal targeting and degradation of EGFR ...

Regeneron Pharmaceuticals Licenses OriGene TrueClone Collection. We believe that full-length cDNAs isolated from cDNA libraries are the most reliable source of authentic coding regions for our critical applications. said Drew Murphy, Vice President of Target Discovery for Regeneron. The OriGene True Clone collection has proven to be an excellent source of full-length human cDNAs for use in Regenerons protein expression and target validation platforms.. ...

Sigma-Aldrich offers abstracts and full-text articles by [Aashiq Hussain, Asif Khurshid Qazi, Nagaraju Mupparapu, Santosh Kumar Guru, Ashok Kumar, Parduman Raj Sharma, Shashank Kumar Singh, Paramjit Singh, Mohd Jamal Dar, Sandip B Bharate, Mohmmad Afzal Zargar, Qazi Naveed Ahmed, Shashi Bhushan, Ram A Vishwakarma, Abid Hamid].

We report the feasibility of screening for the presence of common oncogenic PIK3CA mutations in patients with breast cancer by a simple blood test using BEAMing. Overall, ctDNA was isolated from 109 patient blood samples and a PIK3CA mutation was identified in 28.4%. Of critical importance, testing done in the prospective cohort clearly exemplified the current challenges of locating quality archival tissue samples for biomarker testing. In this case, sufficient tissue was available for only 51 of 60 prospectively enrolled patients (85%). In contrast, BEAMing on ctDNA was successful in the blood samples from all 60 enrolled patients, with a PIK3CA mutation frequency similar to that previously reported (Table 2; refs. 6, 7, 20, 21). Of interest, BEAMing of plasma samples from 2 patients showed 2 separate PIK3CA mutations in each of exons 9 and 20; this is a rare phenomenon but has been previously described (22).. Most critical and with implications for both clinical trial design and clinical ...

PIK-93 is a potent PI3K inhibitor. PIK93 selectively inhibits the type III PI 4-kinase beta enzyme, and small interfering RNA-mediated down-regulation of the individual PI 4-kinase enzymes, revealed that PI 4-kinase beta has a dominant role in ceramide transport between the ER and Golgi.

MSC2360844 is a potent, orally active and selective PI3Kδ inhibitor, with an IC50 of 145 nM. MSC2360844 shows highly selective against a panel of 278 additional kinases. - Mechanism of Action & Protocol.

Overexpression of a dominant-negative PI3Kinase (DP110) resulted in mutants that have impaired regeneration of the intestinal epithelium and are short lived ...

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 neuro

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PI-273 is a first reversibly and specific phosphatidylinositol 4-kinase (PI4KIIα) inhibitor with an IC50 of 0.47 μM. PI-273 can inhibit breast cancer cell proliferation, block the cell cycle and induce cell apoptosis. - Mechanism of Action & Protocol.

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Easy-to-use kits for performing kinase selectivity profiling that rely on the ADP-Glo Kinase Assay technology. Each system includes kinase and substrate pairs in an easy-to-use 8-tube strip format optimized for fast and simple kinase profiling reactions.

Easy-to-use kits for performing kinase selectivity profiling that rely on the ADP-Glo Kinase Assay technology. Each system includes kinase and substrate pairs in an easy-to-use 8-tube strip format optimized for fast and simple kinase profiling reactions.

Onconova therapeutics is developing selective inhibitors of phosphatidylinositol-3-kinase (PI3K) alpha/delta isoforms, called the ON 146 series, for the

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Patients who have breast cancers with double PIK3CA mutations seem to have a more robust response to PI3Kα inhibitors than those with a single PIK3CA mutation, based on an analysis of the phase III SA.... ...

The Akt/PKB signaling pathway is a pathway in cell signaling. Proteins involved include AKT (also known as protein kinase B) and phosphoinositide 3-kinase.

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Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Alpha Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Alpha or Phosphoinositide 3 Kinase Catalytic Alpha Polypeptide or Serine/Threonine Protein Kinase PIK3CA or PIK3CA or EC 2.7.11.1 or EC 2.7.1.153) - The phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha also called p110α is a protein encoded by the PIK3CA gene. It is involved in cell growth, survival, proliferation, motility and morphology. It participates in cellular signaling in response to various growth factors. It is involved in the activation of AKT1 and signaling via insulin receptor substrate (IRS) proteins. It is essential in endothelial cell migration during vascular development through VEGFA signaling. It is required for lymphatic vasculature development.. Phosphatidylinositol 4,5 Bisphosphate 3 Kinase Catalytic Subunit Alpha Isoform (Phosphatidylinositol 4,5 Bisphosphate 3 Kinase 110 kDa Catalytic Subunit Alpha ...

The IUPHAR/BPS Guide to Pharmacology. phosphoinositide-3-kinase regulatory subunit 1 - Phosphatidylinositol kinases. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.

TY - JOUR. T1 - cAMP activates TRPC6 channels via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mitogen-activated protein kinase kinase (MEK)-ERK1/2 signaling pathway. AU - Shen, Bing. AU - Kwan, Hiu Yee. AU - Ma, Xin. AU - Wong, Ching On. AU - Du, Juan. AU - Huang, Yu. AU - Yao, Xiaoqiang. PY - 2011/6/3. Y1 - 2011/6/3. N2 - cAMP is an important second messenger that executes diverse physiological function in living cells. In this study, we investigated the effect of cAMP on canonical TRPC6 (transient receptor potential channel 6) channels in TRPC6-expressing HEK293 cells and glomerular mesangial cells. The results showed that 500 μM8-Br-cAMP, a cell-permeable analog of cAMP,elicited [Ca 2+]i increases and stimulated a cation current at the whole-cell level in TRPC6-expressing HEK293 cells. The effect of cAMP diminished in the presence of the PI3K inhibitors wortmannin and LY294002 or the MEK inhibitors PD98059, U0126, and MEK inhibitor I. 8-Br-cAMP also induced ...

The family of PI3Ks (phosphatidylinositol 3-kinases) was discovered several decades ago, but until now most attention has been given to class I PI3Ks, mainly due to their previously established role in human disorders such as cancer and metabolic diseases. Class II PI3K has therefore been a bit in the shadow of the more intensively studied other families. Nevertheless, the number of reports about class II has started to increase over the past few years and we are now beginning to gain a clearer picture about the role of class II enzymes in different cellular functions and their involvement in human diseases. The fact that class II PI3K generates different second messengers (phosphoinositides) than the other PI3K family members, gives an indication that these enzymes might play a specific role in the regulation of distinct cellular functions. However, there is still a lot to be learned about the molecular mechanism of activation, the cellular function and the physiological and pathological role ...

TY - JOUR. T1 - High-Resolution Structure of the Pleckstrin Homology Domain of Protein Kinase B/Akt Bound to Phosphatidylinositol (3,4,5)-Trisphosphate. AU - Thomas, Christine C.. AU - Deak, Maria. AU - Alessi, Dario R.. AU - van Aalten, Daan M. F.. PY - 2002/7/23. Y1 - 2002/7/23. N2 - The products of PI 3-kinase activation, PtdIns(3,4,5)P3 and its immediate breakdown product PtdIns(3,4)P2, trigger physiological processes, by interacting with proteins possessing pleckstrin homology (PH) domains [1, 2]. One of the best characterized PtdIns(3,4,5)P3/PtdIns(3,4)P2 effector proteins is protein kinase B (PKB), also known as Akt [3-5]. PKB possesses a PH domain located at its N terminus, and this domain binds specifically to PtdIns(3,4,5)P3 and PtdIns(3,4)P2 with similar affinity [6, 7]. Following activation of PI 3-kinase, PKB is recruited to the plasma membrane by virtue of its interaction with PtdIns(3,4,5)P3/PtdIns(3,4)P2 [8-10]. PKB is then activated by the 3-phosphoinositide-dependent pro-tein ...

The PI3K plays a major role in many aspects of cellular biology and is often hyperactivated in human cancers (1, 4). The PI3K family of enzymes has multifunctional roles regulating cellular growth, proliferation, differentiation, motility, intracellular trafficking, and metabolism (4). Three distinct classes of PI3K (class I, II, and III) have been characterized and grouped according to their structure and function. The class IA PI3Ks, which have been implicated in many human cancers, are activated downstream of receptor tyrosine kinases and G protein-coupled receptors (GPCRs) and via interaction with the activated RAS or RHO family of GTPases. Class IA PI3Ks are heterodimers, and each consists of a regulatory subunit p85 (p85α, p55α, or p50α isoforms encoded by PIK3R1, PIK3R2, or PIK3R3, respectively) and a catalytic subunit p110 (p110α, p110β, or p110δ isoforms encoded by PIK3CA, PIK3CB, or PIK3CD, respectively; refs. 1, 4). Class IB comprises a single catalytic subunit, p110δ, that ...

Phosphatidylinositol 3-kinase (PI 3-kinase) is stimulated by insulin and a variety of growth factors, but its exact role in signal transduction remains unclear. We have used a novel, highly specific inhibitor of PT 3-kinase to dissect the role of this enzyme in insulin action. Treatment of intact 3T3-L1 adipocytes with LY294002 produced a dose-dependent inhibition of insulin-stimulated PI 3-kinase (50% inhibitory concentration, 6 microM) with , 95% reduction in the levels of phosphatidylinositol-3,4,5-trisphosphate without changes in the levels of phosphatidylinositol-4-monophosphate or its derivatives. In parallel, there was a complete inhibition of insulin-stimulated phosphorylation and activation of pp70 S6 kinase. Inhibition of PI 3-kinase also effectively blocked insulin- and serum-stimulated DNA synthesis and insulin-stimulated glucose uptake by inhibiting translocation of GLUT 4 glucose transporters to the plasma membrane. By contrast, LY294002 had no effect on insulin stimulation of ...

The PI3K/mTOR pathway is one of the most commonly activated signaling pathway in human cancer. Many players in the PI3K pathway are either amplified, have undergone LOH, or are targeted by somatic or germline alterations (4). These observations led to the development of rapamycin and rapalogs, which are allosteric, irreversible inhibitors of mTORC1, for cancer treatment. Temsirolimus was approved for metastatic renal cell carcinoma in 2007, serving to validate the PI3K/mTOR pathway as a therapeutic target in cancer (17). Despite some success in selected tumor types, rapalogs generally showed very limited anticancer efficacy as single agents and mostly lead to cytostatic effects (18). Negative feedback loops involving S6K have been described to have dramatic effects on drug responses for mTORC1 inhibitors (19). Activated mTORC1 initiates a negative feedback cascade via S6K to downregulate PI3K activity. Treating tumors with rapalogs can result in increased PI3K/Akt activity leading to an enhanced ...

TY - JOUR. T1 - Phosphatidylinositol 3-kinase is a central mediator of NMDA receptor signalling to MAP kinase (Erk1/2), Akt/PKB and CREB in striatal neurones. AU - Perkinton, Michael S. AU - Ip, James K. AU - Wood, Gemma L. AU - Crossthwaite, Andrew J. AU - Williams, Robert J. PY - 2002. Y1 - 2002. N2 - Ca2+ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to these processes. We previously demonstrated that Ca2+-permeable AMPA receptors activate Erkl/2 through a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3-kinase (LY 294002, wortmannin). In addition, pre-treatment of neurones with pertussis toxin inhibited NMDA-induced Erk1/2 activation, indicating a role for heterotrimeric Gi/o proteins. PI 3-kinase ...

Phosphatidylinositol (PI) 3-kinase mediates multiple pathways that regulate many aspects of the cell including rate of metabolism, survival, migration, and proliferation. apoptosis, suggesting that FLII itself is also a survival element. These findings support the model that CISK phosphorylates FLII and activates nuclear receptor transcription and suggest a new cell survival signaling pathway mediated by PI 3-kinase and CISK. Cell death and survival are tightly controlled throughout development, through the action of numerous factors and pathways (1C6). Of these, PI2 3-kinase and its own downstream effectors are being among the most studied widely. PI 3-kinase pathway is vital for success and proliferation of mammalian cells and continues to be implicated in cancers (7C10). Through the legislation of D3-phosphoinositol amounts in cells, PI 3-kinases control the experience of 3-phosphoinositide-dependent kinase and associates from the AGC (cAMP-dependent proteins kinase/proteins kinase G/proteins ...

Service of the PI3K/AKT signal pathway is a known driving force for the progression to castration-recurrent prostate cancer (CR-CaP), which constitutes the major lethal phenotype of CaP. RUNX2 binding to the PIP promoter is increased in FOXO4-KD cells. Indeed, the forced expression of FOXO4 reversed the increased invasiveness of LNCaP/shFOXO4 Rabbit Polyclonal to DECR2 cells; the forced expression of FOXO4 did not alter RUNX2 protein levels, yet it decreased RUNX2 binding to the PIP promoter, resulting in PIP downregulation. Finally, there was a correlation between FOXO4, but not FOXO1 or FOXO3, downregulation and decreased metastasis-free survival in human CaP patients. Our data strongly recommend that improved PI3E/AKT-mediated metastatic invasiveness in Cover can be connected with FOXO4 reduction, and that systems to induce FOXO4 re-expression might suppress Cover metastatic aggressiveness. Intro Prostate tumor (Cover) continues to be the most diagnosed non-cutaneous tumor and the second ...

We recently identified a novel adaptor protein, termed dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), that possesses a Src homology (SH2) domain and a pleckstrin homology (PH) domain. DAPP1 exhibits a high-affinity interaction with PtdIns(3,4,5)P3 and PtdIns(3,4)P2, which bind to the PH domain. In the present study we show that when DAPP1 is expressed in HEK-293 cells, the agonists insulin, insulin-like growth factor-1 and epidermal growth factor induce the phosphorylation of DAPP1 at Tyr139. Treatment of cells with phosphoinositide 3-kinase (PI 3-kinase) inhibitors or expression of a dominant-negative PI 3-kinase prevent phosphorylation of DAPP1 at Tyr139, and a PH-domain mutant of DAPP1, which does not interact with PtdIns(3,4,5)P3 or PtdIns(3,4)P2, is not phosphorylated at Tyr139 following agonist stimulation of cells. Overexpression of a constitutively active form of PI 3-kinase induced the phosphorylation of DAPP1 in unstimulated cells. We demonstrated that Tyr139 of ...

The project aims to understand the molecular and structural mechanism of activation and inhibition of class I phosphoinositide 3 kinases. These lipid kinases are the key signaling element in a diverse array of cellular functions such as cell growth, motility, and, and a validated targets for pharmacological intervention. Deregulation of PI3K pathway is implicated in a variety of diseases including thromboembolism, inflammation, autoimmune diseases and cancer. We determined the structure of PI3Ka in heterodimeric form showing all five domains of p110a in complex with the nSH2 and iSH2 domains of the p85a. We determined the structure of the somatic p110a H1047R/niSH2 mutant alone and in complex with the inhibitor wortmannin. The PI3K enzyme, as the hub of the PI3K/AKT/ mTOR pathway, presents an opportunity where structural biology, enzymology, and inhibitor design converge to both elucidate mechanisms of action and provide initial hits for targeted therapies.. Isoprenoid Pathway as a target of ...

Leucettines, a family of pharmacological inhibitors of DYRKs (dual-specificity tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimers disease. We here report that Leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by LC3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the ULK1 (Unc-51-like kinase) kinase and is sensitive to the PI3K (phosphatidylinositol 3-kinase) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mTOR/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited PIKfyve (phosphatidylinositol-3-phosphate 5-kinase) activity as tested both in vitro and in vivo, ...

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Although interleukin 1 (IL-1) functions have been extensively characterized, the mechanisms by which IL-1 signals are transduced from the plasma membrane to the nucleus are less known. Recent evidence indicates that phosphatidylinositol 3-kinase (PI3-kinase) could be activated by a direct association with the activated IL-1 receptor. In this study we analyzed the effects of IL-1 on the intracellular distribution of PI3-kinase in wild-type Saos-2 human osteosarcoma cells, and in cell clones overexpressing type I IL-1 receptor (IL-1RI). PI3-kinase intracellular distribution displays two distinct patterns. In quiescent cells, PI3-kinase is distributed through the cytoplasm, although a portion is present in the nucleus; following stimulation with IL-1, PI3-kinase is redistributed, increasing in the nuclear compartment. Both immunoblotting and immunofluorescence data indicate that IL-1 causes a rapid and transient translocation of PI3-kinase from the cytoplasm to the nucleus. This phenomenon is ...

TY - JOUR. T1 - Phosphatidylinositol 3-kinase activation is required for stress protocol-induced modification of hippocampal synaptic plasticity. AU - Yang, Ping Chun. AU - Yang, Chih Hao. AU - Huang, Chiung Chun. AU - Hsu, Kuei Sen. PY - 2008/2/1. Y1 - 2008/2/1. N2 - Stress dramatically affects the induction of hippocampal synaptic plasticity; however, the molecular details of how it does so remain unclear. Phosphatidylinositol 3-kinase (PI3K) signaling plays a crucial role in promoting neuronal survival and neuroplasticity, but its role, if any, in stress-induced alterations of long term potentiation (LTP) and long term depression (LTD) is unknown. We found here that inhibitors of PI3K signaling blocked the effects of acute restraint-tail shock stress protocol on LTP and LTD. Therefore, the purpose of the present study is to explore the signaling events involving PI3K in terms of its role in mediating stress protocol-induced alterations of LTP and LTD. We found that stress protocol-induced ...

PIK3CA [ENSP00000263967]. Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature ...

The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014 ...

The phosphoinositide 3-kinase (PI3K) pathway is believed to be of key importance in pediatric glioblastoma. in protein appearance levels of regulatory digestive enzymes involved in glucose and choline rate of metabolism including GLUT1, HK2, LDHA and CHKA. Our results display that by using NMR we can detect unique biomarkers following PI3E pathway inhibition compared to treatment with the DNA-damaging anti-cancer agent TMZ. This is definitely the 1st study reporting that lactate 590-46-5 IC50 590-46-5 IC50 and choline metabolites are potential non-invasive biomarkers for monitoring response to PI3E pathway inhibitors in pediatric glioblastoma. Intro Approximately 40% of all pediatric mind tumors are astrocytomas (gliomas), and of these some 15C20% are malignant gliomas, i.elizabeth. high-grade (WHO grade III and IV) tumors [1], [2]. High-grade gliomas (HGGs) are very aggressive tumors and are one of the leading causes of cancer-related deaths in children with a median survival of just 12C15 ...

Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is extensively explored in cancers. It functions as an important regulator of cell growth, survival and metabolism. Activation of this pathway also predicts poor prognosis in numerous human malignancies. Drugs targeting this signaling pathway have been developed and have shown preliminary clinical activity. Accumulating evidence has highlighted the important role of PI3K in non-Hodgkin lymphoma (NHL), especially in the disease initiation and progression. Therapeutic functions of PI3K inhibitors in NHL have been demonstrated both in vivo and in vitro. This review will summarize recent advances in the activation of PI3K signaling in different types of NHL and the applications of PI3K inhibitors in NHL treatment.

LY3023414 is a small molecule that has been shown in vitro to be a selective ATP-competitive inhibitor of PI3Kα and mTOR, DNA-PK, and other class I PI3K family members. In vitro, LY3023414 has demonstrated inhibitory activity against PI3K and mTOR in tumor cells, as well as antiproliferative activity and cell cycle effects. In addition, in vitro, LY3023414 inhibits the ability of PI3K and mTOR to phosphorylate substrates in the PI3K/mTOR pathway. LY3023414 is being investigated in a phase I clinical trial.

Background:. Esophageal cancer (EC) is an aggressive malignancy with increasing incidence and poor outcome (1). New therapeutic strategies are urgently required. The phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway has been documented as a central hub for the malignant behaviors of cancer cells (2). However, the functional role and therapeutic effect of PI3K/AKT inhibitors in esophageal cancer metastasis is underappreciated.. Aim:. We aim to study the clinical significance of PI3K/AKT signaling pathway in EC metastasis and evaluate the therapeutic effect of PI3K/AKT-targeted therapy.. Methods:. A highly invasive cancer cell line (KYSE410-I3) was established by serial selection of the EC cells invading through the matrigel-coated Boyden chamber. Cell migration and invasion were determined using Boyden chamber migration and invasion assays. Western blot and immunohistochemistry were used to detect protein expressions in cell lysates and in a tissue microarray containing 40 pairs of ...

Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the PIK3R2 gene. PIK3R2 has been shown to interact with: CRKL Cbl gene, Epidermal growth factor, FYN, HER2/neu, Macrophage colony-stimulating factor, and PIK3CD. PIK3R2 mutations were recently shown to be associated with polymicrogyria. GRCh38: Ensembl release 89: ENSG00000105647 - Ensembl, May 2017 Human PubMed Reference:. Mouse PubMed Reference:. Volinia S, Patracchini P, Otsu M, Hiles I, Gout I, Calzolari E, Bernardi F, Rooke L, Waterfield MD (Apr 1992). Chromosomal localization of human p85 alpha, a subunit of phosphatidylinositol 3-kinase, and its homologue p85 beta. Oncogene. 7 (4): 789-93. PMID 1314371. Entrez Gene: PIK3R2 phosphoinositide-3-kinase, regulatory subunit 2 (p85 beta). Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD (Apr 1997). Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, ...

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The phosphatidylinositol 3 -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle ...

The phosphatidylinositol 3 -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle ...

The phosphatidylinositol 4-kinases (PI4Ks) synthesize phosphatidylinositol 4-phosphate (PI4P), a key member of the phosphoinositide family. PI4P defines the membranes of Golgi and trans-Golgi network (TGN) and regulates trafficking to and from the Golgi.. In mammals there are four different PI4K enzymes, two type II enzymes (PI4KIIα and PI4KIIβ) and two type III enzymes (PI4KIIIα and PI4KIIIβ). PI4KIIIβ plays key roles in mediating lipid transport, cytokinesis, maintaining lysosomal identity, and in tandem with Rab GTPases plays key roles in regulating membrane trafficking. PI4KIIIβ is critical for mediating viral replication of a number of RNA viruses through the generation of PI4P enriched viral replication platforms. Small molecule inhibitors of PI4KIIIβ are potent anti-viral agents. Development of PI4KIIIβ as an effective drug target for anti-viral therapeutics requires the generation of highly potent and specific inhibitors.. ...

BACKGROUND: Exposure to intermittent hypoxia (IH) may enhance cardiac function and protects heart against ischemia-reperfusion (I/R) injury. To elucidate the underlying mechanisms, we developed a cardioprotective IH model that was characterized at hemodynamic, biochemical and molecular levels. METHODS: Mice were exposed to 4 daily IH cycles (each composed of 2-min at 6-8% O2 followed by 3-min reoxygenation for 5 times) for 14 days, with normoxic mice as controls. Mice were then anesthetized and subdivided in various subgroups for analysis of contractility (pressure-volume loop), morphology, biochemistry or resistance to I/R (30-min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion and measurement of the area at risk and infarct size). In some mice, the phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin was administered (24 µg/kg ip) 15 min before LAD. RESULTS: We found that IH did not induce myocardial hypertrophy; rather both contractility and ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014 ...

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014 ...

Introduction: This study describes the development of a novel dual specificity kinase inhibitor, ON 123300, which exhibits potent activity against Mantle Cell Lymphomas (MCLs) both in vitro and in vivo. Mantle cell lymphoma is genetically characterized by the t(11;14)(q13;q32) chromosomal translocation which results in constitutive overexpression of cyclin D1. In addition, MCLs also activate other pathways, including aberrant B-Cell Receptor and PI3K/AKT/mTOR signaling. As a result, MCL has a poor clinical outcome with a median survival of 4-5 years. In this study, we show that ON123300, which inhibits both CDK4/6 and PI3K-α (the predominant PI3K catalytic subunit expressed in MCL cells), is a superior inducer of apoptosis of MCL cells when compared to PD0332991, a selective inhibitor of CDK4/6 kinases.. Experimental Procedures: We examined the effects of PD 0332991 and ON123300 on cell cycle progression, modulation of the Rb and PI3K/AKT pathways, and the induction of apoptosis in the Granta ...

CNTRL-FGFR1 induces AML and T-cell lymphoma in murine and individual progenitor cells. to successfully treating this almost invariably lethal disease. Intro Constitutive activation of FGFR1 kinase in hematopoietic stem cells (HSC) resulting from chromosome translocations including 8p11 prospects to myeloproliferative neoplasms (MPN) that inevitably progress to acute myeloid leukemia (AML) and is frequently accompanied by T- and B-cell lymphomas. Overall survival is definitely poor due to resistance to current restorative regimens. The hallmark of FGFR1-related neoplasms is definitely bilineage disease, GX15-070 in which tumor cells from both lineages harbor the chimeric FGFR1 fusion gene, suggesting a common stem/progenitor source. fuses to more than 11 partner genes,1 such as ZMYM2-FGFR1, BCR-FGFR1, and CNTRL-FGFR1. Constitutive activation of FGFR1 is definitely believed to be the primary initiation event that drives disease development, although its oligoclonal nature suggests other genetic ...

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Background In mouse the cytokine interleukin-7 (IL-7) is necessary for generation of B lymphocytes, but human IL-7 does not appear to have this function. amino acid identity and are expressed in cell lines and main hematopoietic lineage cells differentially. Genes Selumetinib for FIGLER homologs had been discovered in macaque, orangutan, chimpanzee, mouse, rat, pup, rooster, toad, and puffer seafood databases. The nonhuman FIGLER homologs talk about 38C99% general amino acid identification with their individual counterpart. Bottom line The extracellular domains structure and lack of recognizable cytoplasmic signaling motifs in associates from the extremely conserved FIGLER gene family members recommend a trophic or cell adhesion function for these substances. History Interleukin-7 (IL-7) is normally a nonredundant cytokine necessary for the era of B and T lineage cells in mice [1-5]. Although Selumetinib IL-7 is vital for T cell advancement in humans, individual B cell advancement is unaffected ...

The protein encoded by this gene catalyzes the phosphorylation of phosphatidylinositol-5-phosphate on the fourth hydroxyl of the myo-inositol ring to form phosphatidylinositol-5,4-bisphosphate. This gene is a member of the phosphatidylinositol-5-phosphate 4-kinase family. The encoded protein sequence does not show similarity to other kinases, but the protein does exhibit kinase activity. Additionally, the encoded protein interacts with p55 TNF receptor. [provided by RefSeq, Jul 2008 ...

Visfatin is an adipocytokine capable of mimicking the glucose-lowering effects of insulin and activating the pro-survival kinases phosphatidylinositol

Ito, K., Caramori, G. and Adcock, I.M. (2007) Therapeu tic potential of phosphatidylinositol 3-kinase inhibitors in inflammatory respiratory disease. The Journal of Phar macology and Experimental Therapeutics, 321, 1-8. Epub 4 October 2006. doi10.1124/jpet.106.111674