The serine/threonine kinase Akt (PKB/Rac) has been implicated as playing a role in the insulin-signaling pathway to glucose transport. Little is known regarding the regulation of Akt kinase activity in insulin-sensitive tissues, such as skeletal muscle, or whether this regulation is altered in insulin-resistant states such as NIDDM. We examined the effect of insulin on Akt kinase activity in skeletal muscle from six NIDDM patients and six healthy subjects. Whole-body insulin sensitivity, assessed by the euglycemic-hyperinsulinemic clamp, was significantly lower in NIDDM subjects (P , 0.001), and this was accompanied by impaired in vitro insulin-stimulated glucose transport in skeletal muscle. In both groups, insulin induced a significant increase in Akt kinase activity, but the response to maximal insulin (60 nmol/1) was markedly reduced in skeletal muscle from NIDDM subjects (66% of control levels, P , 0.01). Impaired Akt kinase activity was not accompanied by decreased protein expression of ...
Serine 1450 phosphorylation is critical for Akt-induced N-CoR misfolding.A, Serine to alanine substitution at 1450 abrogated Akt-induced N-CoR misfolding. Relat
Maintenance of skeletal muscle mass is dependent upon a balance between anabolic and catabolic processes and signaling through the Akt (protein kinase B, PKB)/mTOR (mammalian target of rapamycin) pathway is believed to influence protein synthesis as well as protein degradation in skeletal muscle [1 - 3]. The Akt family consists of three different isoforms, Akt1, Akt2 and Akt3 (PKBα, β, γ) encoded by separate genes [4]. Gene deletion studies have indicated a role for both Akt1 and Akt2 in growth and skeletal muscle size [5] and overexpression of Akt1 has been shown to result in skeletal muscle hypertrophy [6]. Akt activity is regulated by phosphorylation both at a threonine site (T308 for Akt1) located in the central catalytic domain (see e.g. [4,7]) and at a serine site (S473 for Akt1) located in the C-terminal hydrophobic regulatory domain (see e.g. [4,8]). Phosphorylations of both sites are believed to be necessary for full activation of Akt kinase activity [9] although this may not be true ...
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 ...
Aberration of receptor tyrosine kinases (RTKs), PTEN (phosphatase and tensin homolog deleted on chromosome 10), and PIK3CA (encodes the p110 subunit of phosphatidylinositol 3-kinase [PI3K]) frequently contribute to tumor progression through their ability to regulate the intracellular level of phosphatidylinositol-3,4,5- triphosphate (PIP3). PIP3 subsequently recruits 3-phosphoinositide- dependent kinase-1 (PDK-1), a serine/threonine kinase, to the plasma membrane and initiates PDK-1 kinase activity to phosphorylate AKT within the activation loop of the catalytic domain at the residue threonine-308 (T308). The mammalian target of rapamycin (mTOR) plays a critical role in the PI3K/AKT pathway. The mTOR kinase is present as two protein complexes, TORC1 and TORC2. The TORC1 complex is activated by PI3K/AKT and phosphorylates p70S6K and 4E-BP1 to modulate protein translation whereas the TORC2 complex phosphorylates AKT in the regulatory domain at residue serine 473 (S473). Phosphorylation of AKT at ...
The Akt/PKB kinase is a well-characterized effector of phosphoinositide 3-kinase (PI3K), and its deregulation plays important roles in the pathogenesis of human cancers. PI3K is necessary for the activation of Akt/PKB, and current models suggest that phosphatidylinositol-3,4,5-triphosphates produced upon growth factor stimulation recruit Akt/PKB to the plasma membrane by binding to its N-terminal pleckstrin homology (PH) domain. At the membrane, Akt/PKB is phosphorylated on two key residues: Thr308 (T308) of the activation loop by PDK1 (1, 2) and Ser473 (S473) in the hydrophobic motif of the C-terminal tail by a kinase whose identity has been elusive. The role of S473 phosphorylation is controversial, but there is an emerging view that it precedes the phosphorylation of T308 and is important for the recognition and activation of Akt/PKB by PDK1 (3-5).. The molecular identity of the S473 kinase (S473K), at times referred to as "PDK2" or the "hydrophobic motif (HM) kinase," has been hotly debated ...
The Akt (also referred to as protein kinase B) family of serine/threonine protein kinases is highly conserved in evolution.5 Akt1 and Akt2 share extensive sequence homology at the amino acid level, whereas Akt3 is slightly more divergent in structure and is expressed as a splice variant that lacks a regulatory phosphorylation site.6 Akt protein kinases are stimulated by a number of receptor tyrosine kinases, and this is mediated by the action of phosphatidylinositol 3-kinase (PI3K). PI3K phosphorylates inositol lipids that activate Akt directly by binding to its pleckstrin homology domain and promoting its translocation to the membrane and indirectly by activating the protein kinases that phosphorylate Akt. In the heart, Akt activation is regulated by insulin and nutritional status,7 exercise training,8-10 pressure overload,11 and advanced disease.12,13 In turn, Akt signaling regulates myocyte size, at least in part, through activation of mTOR-dependent progrowth pathways14,15 and suppression of ...
Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis.: Here, we show that CDK2, an S-phase cyclin-dependent kina
Akt reportedly plays key roles in various cellular functions, including glucose transport, glycogen synthesis, DNA synthesis, antiapoptotic activity, and cell proliferation. Thus, the role of Akt is not limited to the metabolic actions of insulin, and intensive studies have focused on Akt in various fields of cell biology, tissue development, and so on. Several reports have described tissue-specific findings in mice transgenic for Akt. The heart (39-41) and pancreas (42,43), in which an active mutant of Akt was overexpressed, showed marked tissue enlargement. To study the role of hepatic Akt, constitutively active Akt was overexpressed selectively in the liver, and the resultant phenotype was investigated. We cannot rule out the possibility that myr-Akt stimulates some signals that endogenous Akt does not; however, because Akt is phosphorylated, translocated to the membrane fraction, and then transmits the signal(s), the overexpression of myr-Akt rather than wild-type Akt is more physiological, ...
Our data reveal a novel PS1 function by which this protein stimulates PI3K/Akt signaling and promotes cell survival. This conclusion is supported by the following observations: (1) absence of PS1 results in low levels of phosphorylated Akt and increased apoptosis; (2) exogenous PS1 stimulates Akt phosphorylation and rescues PS1 null cells from apoptosis; (3) a constitutively active PI3K restores Akt activation and suppresses apoptosis induced by the absence of PS1; (4) pharmacological inhibition of either PI3K or Akt prevents the PS1‐dependent Akt phosphorylation and caspase‐3 inactivation, indicating that the PI3K/Akt pathway mediates the anti‐apoptotic effects of PS1.. Cadherin-cadherin interactions initiate a cascade of signaling events that result in increased cadherin/PI3K association, activation of PI3K/Akt signaling and increased cell survival (Pece et al, 1999; Peluso et al, 2001; Kovacs et al, 2002; Tran et al, 2002; Yap and Kovacs, 2003). Our data that cadherin overexpression ...
The Alpha SureFire® Ultra™ HV Multiplex p-Akt 1/2/3 (Ser473) + Total Akt 1 assay kit is used to measure both the phosphorylation (Ser473) and total levels of endogenous Akt in cellular lysates. The kit measures phosphorylation on Ser473 of Akt 1/2/3, and total levels of Akt 1 only. The assay is an ideal system for the screening of modulators of receptor activation (e.g. agonists and antagonists) as well as agents acting intracellularly, such as small molecule inhibitors of signal transduction. The assay will measure Akt (Ser473) activation by either recombinant or endogenous receptors, and can be applied to primary cells.
Akt, or protein kinase B, is a multifunctional serine-threonine protein kinase implicated in a diverse range of cellular functions including cell metabolism, survival, migration, and gene expression. However, the in vivo roles and effectors of individual Akt isoforms in signaling are not explicitly clear. Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis as well as severe peripheral vascular disease. Akt1 knockout (Akt1-/-) mice also have reduced endothelial progenitor cell (EPC) mobilization in response to ischemia, and reintroduction of WT EPCs, but not EPCs isolated from Akt1-/- mice, into WT mice improves limb blood flow after ischemia. Mechanistically, the loss of Akt1 reduces the basal phosphorylation of several Akt substrates, the migration of fibroblasts and ECs, and NO release. Reconstitution of Akt1-/- ECs with Akt1 rescues the defects in substrate phosphorylation, cell migration, and NO release. Thus, the Akt1 ...
1H10: High Resolution Structure of the Pleckstrin Homology Domain of Protein Kinase B/Akt Bound to Phosphatidylinositol (3,4,5)-Trisphosphate
Surucu B, et al. (2008) In vivo analysis of protein kinase B (PKB)/Akt regulation in DNA-PKcs-null mice reveals a role for PKB/Akt in DNA damage response and tumorigenesis. J Biol Chem 283, 30025-33 ...
These observations emphasize the sturdy association among the balance of Akt and mTORC1 routines and the development of steatosis. When Akt dominates above mTORC1, steatosis ensues, whilst when mTORC1 overshadows Akt, fat deposition is suppressed. Other designs of Akt suppression in the liver also result in a reduction in TG accumulation together with glucose intolerance equivalent to that of the Tsc12/two mice. Hence, inhibition of hepatic Akt action by any quantity of mechanisms leads to complete hepatic insulin resistance. On the opposite, growing Akt function in hepatocytes by immediate or oblique implies promotes lipogenesis and steatosis. These conclusions help our conclusion that the protecting result of mTORC1 from diet plan-induced steatosis is mediated by means of the inhibition of Akt signaling and underscore the prospective for focusing on Akt pharmacologically in the treatment method of steatosis. Rapamycin is frequently employed as an immunosuppressant adhering to renal transplant, ...
IC50: AKT1 32 nM, AKT2 17 nM, AKT3 47 nM, PKA 20 nMThe serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therap
Some Akt inhibitors have produced functional cardiovascular effects such as marked hypotension that may limit their clinical benefit. There are no current data on whether this autonomic failure presents in humans at clinically used doses. We will test the hypothesis that Akt inhibition causes an acute decrease in sympathetic tone and lowers blood pressure ...
AKTRES is a biological substudy of the early effects and determinants of AKT inhibition using afuresertib in combination with chemotherapy in patients with
Related Articles Design, synthesis, in silico pharmacokinetics prediction and biological evaluation of 1,4-dihydroindeno[1,2-c]pyrazole chalcone as EGFR /Akt pathway inhibitors. Eur J Med Chem. 2018 Dec ...
Purchase AKT1 antibodies for various cancer, cardiovascular, cell biology, neuroscience & other research areas. Contact Abgent for antibody services and more!
Haplotype: (AKT1_1251C,T) - ( AKT1_IVS14+32G,A) - ( AKT1_IVS14+66C,G) - ( AKT1_IVS14+93C,T) - ( AKT1_IVS+95-98delCTCA)(C-G-C-C-del), (AKT1_1251C,T) - ( AKT1_IVS14+32G,A) - ( AKT1_IVS14+66C,G) - ( AKT1_IVS14+93C,T) - ( AKT1_IVS14+98A,G)(C-G-C-C-A), (AKT1_1251C,T) - ( AKT1_IVS14+32G,A) - ( AKT1_IVS14+66C,G) - ( AKT1_IVS14+93C,T) - ( AKT1_IVS14+98A,G)(C-G-G-C-A), (AKT1_1251C,T) - ( AKT1_IVS14+32G,A) - ( AKT1_IVS14+66C,G) - ( AKT1_IVS14+93C,T) - ( AKT1_IVS14+98A,G) - ( AKT1_IVS14+105_106ins_CTCAC or CTCAG)(C-G-C-C-G-insCTCAG ...
AKT (phospho Ser473) antibody (AKT serine/threonine kinase 1) for ICC/IF, IHC-Fr, IHC-P, WB. Anti-AKT (phospho Ser473) pAb (GTX28932) is tested in Human, Mouse samples. 100% Ab-Assurance.
Phospho-AKT1 (Ser473), PE, clone: SDRNR, eBioscience™ 100 Tests; PE Phospho-AKT1 (Ser473), PE, clone: SDRNR, eBioscience™ Primary Antibodies Ad to Ak
The AKT family of serine threonine kinases is of critical importance with regard to growth factor signaling, cell proliferation, survival and oncogenesis. Engag
Akt1通过抑制凋亡过程从而参与细胞存活途径。Akt1亦能诱导蛋白合成通路,故其在导致骨骼肌肥大及的一般组织生长的细胞通路中是一种重要信号蛋白。因其可以阻断凋亡并继而促进细胞存活,现已表明Akt1在多种肿瘤中起到主要作用。Akt(先亦被称为Akt1)首先是在转化逆转录病毒AKT8中被鉴定为癌基因的[3]。 Akt2在胰岛素信号通路中是一重要的信号分子。需要其来诱导葡萄糖转运。在敲除Akt1但具正常Akt2的小鼠中,血糖稳态不受干扰,但动物体型会较小,这与Akt1在生长中起得作用是一致的。相反,Akt2缺失但具有正常Akt1的的小鼠生长略缺陷且表现出糖尿病表型(胰岛素抵抗),这从另一方面印证了Akt2对胰岛素受体信号通路更具特异性的这一设想[4]。 Akt3似乎主要在脑中表达,但其作用仍未明晰。有报道显示Akt3缺失的小鼠脑部较小[5]。 ...
Information and case study data for the PTMScan Direct PI3K / Akt Service offered by CST, which allows for targeted screening of 105 proteins within the Akt pathway.
Examination of the correlation between Akt Thr308 and Ser473 phosphorylation and the phosphorylation of Akt substrates. Triplicate samples of normal and patient
Akt-2 is a medicine available in a number of countries worldwide. A list of US medications equivalent to Akt-2 is available on the Drugs.com website.
购买我们的重组人AKT1蛋白。Ab79792为有活性的全长蛋白,在杆状病毒感染sf9细胞中生产并经过Functional Studies, SDS-PAGE, Western blot实验验证。中国80%以上现货。
购买我们的重组人AKT3蛋白。Ab43621为全长蛋白,在杆状病毒感染sf9细胞中生产并经过Western blot实验验证。Abcam提供免费的实验方案,操作技巧及专业的支持。
陶素的所有产品和服务仅用于科学研究,我们不为任何其他用途提供产品和服务(也不为任何个人提供产品和服务 ...
Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the
Further evaluation of PI3K/AKT/mTOR pathway inhibitors is required to confirm whether the patterns of sensitivity observed in preclinical studies can be applied in the clinic. Although many early-phase trials have independently failed to identify a distinct association between clinical response and the most common alterations in the PI3K pathway (PIK3CA mutation and PTEN loss), a pooled analysis of 140 patients with various breast and gynecologic cancers treated with different PI3K/AKT/mTOR inhibitors identified an increased rate of RECIST-defined clinical responses among patients with PIK3CA mutations (75). A follow-up study pooling 1,012 patients with diverse cancers treated with PI3K/AKT/mTOR pathway inhibitors also identified an increased rate of response among tumors with PIK3CA H1047R mutation, but not those with other PIK3CA mutations or concurrent PIK3CA and KRAS mutations (76). The findings of these association studies have sparked interest in the research community; however, additional ...
The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, ...
The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, ...
RAC Gamma Serine/Threonine Protein Kinase (Protein Kinase Akt 3 or Protein Kinase B Gamma or RAC PK Gamma or STK 2 or AKT3 or EC 2.7.11.1) - Pipeline Review, H2 2017 Size and Share Published in 2017-08-29 Available for US$ 3500 at Researchmoz.us
3589 In women, endometrial cancer is the fourth in importance among all types of cancer. While most patients with disease recurrence after primary therapy are incurable, there is a subset of patients treated with surgery only who have recurrence confined to the pelvis that may be cured with appropriate radical pelvic irradiation. However, recurrent endometrial carcinoma, non-response to irradiation, age of the women or the presence of metastases are reasons that lead to the use chemotherapeutic agents. A major difficulty with chemotherapy is cellular resistance to chemotherapeutic drugs, and the mecanisms involved remain to be elucidated. Three isoforms of serine/threonine protein kinase Akt have been identified: Akt1, Akt2, Akt3, which are expressed and regulated differently in normal and cancer cells. The activity of Akt has been shown to suppress apoptosis and could be involved in chemoresistance. We have evaluated the role of Akt isoforms in chemoresistance of endometrial carcinoma cells, ...
Accumulated evidence indicates that, by the phosphorylation of its physiological substrates, Akt promotes cell survival, proliferation and angiogenesis. While a number of Akt targets have been identified, the mechanism by which Akt regulates cell survival and growth and induces malignant transformation still remains elusive. During the last 5 years, I have shown that AKT1 cross-talks with Src/Stat3 pathway. AKT1 is a direct target gene of Stat3. Protein/mRNA levels and promoter activity of AKT1 are significantly induced by constitutively active Src and Stat3. Knockdown of Stat3 or dominant-negative Stat3 reduced AKT1 expression induced by constitutively active Src. Blockage of AKT1 expression largely reduced Stat3 function in cell survival and angiogenesis. Furthermore, I have shown that proapoptotic protein 24p3 is a major target of Akt to mediate IL3 signaling in hematopoietic cells. Forkhead transcription factor FOXO3a directly binds to and activates 24p3 promoter leading to expression of 24p3 in
Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects. We demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects
Non-small cell lung cancers (NSCLC) are associated with constitutive activation of the phosphoinositide 3-kinase (PI3K) → Akt → mTOR pathway (1-3). The PI3K p85 regulatory subunit contains Src homology 2 (SH2) domains that interact with pYXXM sequences on activated receptor tyrosine kinases (RTK), such as the epidermal growth factor receptor (EGFR; ref 4). In turn, PI3K p85-mediated inhibition of the PI3K p110 catalytic subunit is relieved and p110 phosphorylates Akt (4). PI3K p110 also binds directly to Ras, linking PI3K signaling to the activation of Ras (5). Effective treatment of NSCLC with EGFR inhibitors is associated with suppression of PI3K activity and resistance to these inhibitors occurs with reactivation of the PI3K → Akt signaling pathway (4). The mTOR complex 1 (mTORC1) is a downstream effector of Akt, as well as other inputs, that regulates cell growth and is often dysregulated in human cancers (6). In this regard, agents that block the PI3K → Akt → mTOR pathway are ...
AKT (a serine/threonine protein kinase) has become a popular target for drug discovery campaigns, due to the fact that AKT inhibitors may help to treat a number of cancers. In this application note BioTek demonstrates an automated homogeneous assay to probe AKT phosphorylation at its serine 473 residue using endogenous levels of kinase expression within human primary HUVEC cells.
The observation of three distinct patterns (nuclear, cytoplasmic, and both) of localization of FKHR1 suggested the possibility that its intracellular localization might be regulated by extracellular growth signals or cell cycle progression. This hypothesis was tested by determining the localization of FKHR1-HA in serum-starved cells. CV1 cells transiently transfected with FKHR1-HA subsequently were maintained in serum-free medium for 24 hr before fixation. Under conditions of serum starvation FKHR1-HA was restricted to the nucleus in greater than 90% of the cells (Fig. 1 B and I). Moreover, treatment of serum-starved cells expressing FKHR1-HA with either 50 nM insulin-like growth factor I (Fig. 1O) or 10% serum (data not shown) for periods of time as short as 15-30 min was sufficient to cause export of FKHR1-HA from the nucleus in 70% of cells.. The growth factor stimulation of FKHR1-HA nuclear export could reflect either a passive process, such as inhibition of DNA binding leading to a ...
FSH stimulation of granulosa cells (GCs) results in increased hypoxia-inducible factor (HIF)-1alpha protein levels and HIF-1 activity that is necessary for up-regulation of certain FSH target genes including vascular endothelial growth factor. We report that the role of the phosphatidylinositol (PI)-3-kinase/AKT pathway in increasing HIF-1alpha protein in FSH-stimulated GCs extends beyond an increase in mammalian target of rapamycin-stimulated translation. FSH increases phosphorylation of the AKT target mouse double-minute 2 (MDM2); a phosphomimetic mutation of MDM2 is sufficient to induce HIF-1 activity. The PI3-kinase/AKT target forkhead box-containing protein O subfamily 1 (FOXO1) also effects the accumulation of HIF-1alpha as evidenced by the ability of a constitutively active FOXO1 mutant to inhibit the induction by FSH of HIF-1alpha protein and HIF-1 activity. Activation of the PI3-kinase/AKT pathway in GCs by IGF-I is sufficient to induce HIF-1alpha protein but surprisingly not HIF-1 activity.
AKT-mediated phosphorylation of ATG4B impairs mitochondrial activity and enhances the Warburg effect in hepatocellular carcinoma cells
12. Bergamot Polyphenolic Fraction Enhances Rosuvastatine-Induced Effect on LDL-Cholesterol, LOX-1 Expression and Protein Kinase B Phosphorylation in Patients with Hyperlipidemia: Gliozzi M1, Walker R, Muscoli S, Vitale C, Gratteri S, Carresi C, Musolino V, Russo V, Janda E, Ragusa S, Aloe A, Palma E, Muscoli C, Romeo F, Mollace V. This paper has been supported by PON a3_00359; PON03PE_00078_1 and PON03PE_00078_2 ...
rIPC [remote IPC (ischaemic preconditioning)] has been shown to invoke potent myocardial protection in animal studies and recent clinical trials. Although the important role of PI3K (phosphoinositide 3-kinase)/Akt activation in the cardioprotection afforded by local IPC is well described, our understanding of the intracellular signalling of rIPC remains incomplete. We therefore examined the hypothesis that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β (glycogen synthase kinase 3β) signalling pathway, activation of which is associated with nuclear accumulation of β-catenin. rIPC was induced in mice using four cycles of 5 min of ischaemia and 5 min of reperfusion of the hindlimb using a torniquet. This led to reduced infarct size (19±4% in rIPC compared with 39±7% in sham; P,0.05), improved functional recovery and reduced apoptosis after global I/R (ischaemia/reperfusion) injury using a Langendorff-perfused mouse heart model. These effects were reversed by ...
Clinical trial design. The success of tyrosine kinase inhibitors, such as erlotinib and imatinib, and the strong rationale to target the PI3K/Akt/mTOR pathway has fed optimism that inhibitors of serine/threonine kinases, such as PI3K, PDK-1, Akt, or mTOR, might have clinical use for cancer patients. Because these drugs are predicted to modulate a target and do not cause direct DNA damage like most standard chemotherapies, the design of clinical trials with PI3K/Akt/mTOR pathway inhibitors should reflect their biological activities. Based on numerous preclinical studies, pathway inhibitors are likely to be most effective in patients whose tumors bear activation of the pathway. Thus, phase I protocols with inhibitors of the PI3K/Akt/mTOR pathway should determine the biologically effective dose and the maximum tolerated dose and should determine the relationship between these doses. Although it can be argued that determining a tolerated biologically effective dose is sufficient for a targeted ...
The phosphatidylinositol-3-kinase /protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway plays an important role in cell proliferation, growth, and angiogenesis.
Tuberin exists as a phosphoprotein, the target of both serine/threonine and tyrosine kinases (31) . Our data are consistent with that of others, which indicate that at least one of these kinases is Akt, a downstream effector of the PI3K signaling pathway (33, 34, 35, 36) . Tuberin contains three recognition sites for Akt that are also potential 14-3-3 binding sites. Using a novel protein domain array, a tuberin peptide containing Ser939 bound to 14-3-3 in a phosphorylation-specific manner. All seven 14-3-3 isoforms recognized tuberin in GST-pull-down assays, and at least one of these, 14-3-3γ, recognized tuberin in fibroblasts (NIH3T3) as well as mammary (MCF-7) and kidney epithelial cells (TRKE) from mouse, human, and rat, respectively. The interaction between 14-3-3γ and tuberin was effectively competed with phosphorylated but not unphosphorylated Ser939 peptide. Endogenous tuberin could also be coimmunoprecipitated with 14-3-3 in kidney epithelial cell lysates. While in submission, our data ...
As its role in tumor progression emerges, the PI3K/PKB (Akt) pathway presents an appealing cancer therapeutic target. Recent studies have investigated the mechanisms underlying the tumor-promoting effects of this pathway. PKB triggers a network that positively regulates G1/S cell cycle progression t …