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

TY - JOUR. T1 - Polycystin-1 mitigates damage and regulates CTGF expression through AKT activation during cardiac ischemia/reperfusion. AU - Aránguiz, P.. AU - Romero, P.. AU - Vásquez, F.. AU - Flores-Vergara, R.. AU - Aravena, D.. AU - Sánchez, G.. AU - González, M.. AU - Olmedo, I.. AU - Pedrozo, Z.. PY - 2021/1/1. Y1 - 2021/1/1. N2 - During ischemia/reperfusion (I/R), cardiomyocytes activate pathways that regulate cell survival and death and release factors that modulate fibroblast-to-myofibroblast differentiation. The mechanisms underlying these effects are not fully understood. Polycystin-1 (PC1) is a mechanosensor crucial for cardiac function. This work aims to assess the role of PC1 in cardiomyocyte survival, its role in profibrotic factor expression in cardiomyocytes, and its paracrine effects on I/R-induced cardiac fibroblast function. In vivo and ex vivo I/R and simulated in vitro I/R (sI/R) were induced in wild-type and PC1-knockout (PC1 KO) mice and PC1-knockdown (siPC1) ...

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, ...

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.

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, ...

In this study, we show that AKT overexpression alone in tamoxifen-sensitive, ER+ breast cancer cells is sufficient to confer tamoxifen-resistant cell proliferation. To identify genes that may be involved in AKT-induced tamoxifen resistance, we used microarray analysis to identify differentially expressed genes. Functional analysis revealed that two main biologic processes are altered: cell proliferation and cell motility (Supplementary Table S2), supporting our in vitro observations seen in AKT-expressing cells. Because expression of both AKT1 and AKT3 are significantly greater in patient breast tumors (Fig. 1) and because tumors exhibit greater cell proliferation and motility than normal cells, it was not surprising that these same differentially expressed genes also strongly correlated with breast carcinoma as compared with normal breast tissue in existing tumor cohorts, further validating our array data (Fig. 5B and Supplementary Fig. S4).. From our IPA analysis, estrogen and NFκB were ...

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

TY - JOUR. T1 - Regulation of insulin action by ceramide. T2 - Dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. AU - Stratford, Suzanne. AU - Hoehn, Kyle L.. AU - Liu, Feng. AU - Summers, Scott A.. PY - 2004/8/27. Y1 - 2004/8/27. N2 - The sphingolipid ceramide negatively regulates insulin action by inhibiting Akt/protein kinase B (PKB), a serine/threonine kinase that is a central regulator of glucose uptake and anabolic metabolism. Despite considerable attention, the molecular mechanism accounting for this action of ceramide has remained both elusive and controversial. Herein we utilized deletion constructs encoding two different functional domains of Akt/PKB to identify which region of the enzyme conferred responsiveness to ceramide. Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt/PKB by two independent mechanisms. First, using the isolated pleckstrin homology domain, we found that ...

PTEN/MMAC1 is a tumor suppressor gene that is mutated in a variety of cancers. PTEN encodes a phosphatase that recognizes phosphoprotein substrates and the phospholipid, phosphatidylinositol-3,4,5-triphosphate. PTEN inhibited cell growth and/or colony formation in all of the epithelial lines tested with one exception. The decrease in cellular proliferation was associated with an induction of apoptosis and an inhibition of signaling through the phosphatidylinositol 3′-kinase pathway. Akt/protein kinase B, a gene whose antiapoptotic function is regulated by phosphatidylinositol-3,4,5-triphosphate, was able to rescue cells from PTEN-dependent death. PTEN, therefore, appears to suppress tumor growth by regulating phosphatidylinositol 3′-kinase signaling. ...

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 ...

Amplification or overexpression of HER-2/neu in cancer cells confers resistance to apoptosis and promotes cell growth. The cellular localization of p21Cip1/WAF1 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Here we show that HER-2/neu-mediated cell growth requires the activation of Akt, which associates with p21Cip1/WAF1 and phosphorylates it at threonine 145, resulting in cytoplasmic localization of p21Cip1/WAF1. Furthermore, blocking the Akt pathway with a dominant-negative Akt mutant restores the nuclear localization and cell-growth-inhibiting activity of p21Cip1/WAF1. Our results indicate that HER-2/neu induces cytoplasmic localization of p21Cip1/WAF1 through activation of Akt to promote cell growth, which may have implications for the oncogenic activity of HER-2/neu and Akt.

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

RESULTS We found a significant increase of FTO mRNA and protein levels in muscle from type 2 diabetic patients, whereas its expression was unchanged in obese or type 1 diabetic patients. Moreover, insulin or glucose infusion during specific clamps did not regulate FTO expression in skeletal muscle from control or type 2 diabetic patients. Interestingly, rosiglitazone treatment improved insulin sensitivity and reduced FTO expression in muscle from type 2 diabetic patients. In myotubes, adenoviral FTO overexpression increased basal protein kinase B phosphorylation, enhanced lipogenesis and oxidative stress, and reduced mitochondrial oxidative function, a cluster of metabolic defects associated with type 2 diabetes.. ...

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 ...

FIGURE 3. The Keap1-independent regulation of Nrf2 protein stability. As illustrated, the Keap1-independent regulation of Nrf2 protein stability may occur via two pathways. One pathway is that GSK-3β phosphorylates Nrf2 enabling it to be recognized by β-TrCP and ubiquitylated by the β-TrCP-Cul1 E3 ubiquitin ligase complex for the eventual proteasomal degradation. The other pathway is dependent on Hrd1, an E3 ligase that ubiquitylates Nrf2 for proteasomal degradation. Hence, both pathways are negative regulators of Nrf2 protein stability, and inhibition of these pathways would cause Nrf2 activation and increased antioxidant gene expression. 2.3.1. β-TrCP-Cul1-Dependent Pathway Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway causes Nrf2 activation, increasing ARE-driven antioxidant gene transcription [20]. A critical mediator in the PI3K/Akt-dependent pathway is glycogen synthase kinase-3beta (GSK-3β), which phosphorylates Nrf2 [21]. This phosphorylation enables Nrf2 to be ...

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.

Phosphatidylinositol-3 kinase (PI3-K) and protein kinase B (Akt) activation not only stimulate NO production, but they also inhibit glycogen synthase kinase-3β (GSK3β) (8). Similarly, activation of canonical Wnt signaling inactivates GSK3β (9). Wnts are secreted glycoproteins known to regulate hematopoiesis and stem cell function (9). In the unstimulated cell, GSK3β phosphorylates and accelerates degradation of HIF-1α and β-catenin (9,10). Inhibition of GSK3β leads to cytosolic accumulation and nuclear translocation of these transcription factors in a manner that increases EPC survival, proliferation, differentiation, mobilization, and adhesion (11-13). EPCs pretreated with GSK inhibitors or EPCs that are genetically modified to overexpress VEGF or inactive GSK3β enhance vasculogenesis, augment reendothelialization, and reduce neointimal formation (11-13).. Diabetes is associated with reduced endothelial NO bioavailability and PI3-K/Akt activity, and EPCs are defective and reduced in ...

The EGFR/PI3K/AKT cascade has been shown to confer cancer cell survival and to enhance resistance to chemotherapy. Therefore, EGFR/PI3K/AKT inhibitors have been developed to act as potential molecular targeting drugs for cancer therapy or have been used in combination with cytotoxic drugs to enhance the chemotherapeutic response. For example, cisplatin combined with EGFR or PI3K inhibitors may reduce the resistance to cisplatin in gliomas (35), pancreatic cancer (36), ovarian cancer (37), and lung cancer cells (38) in vitro. Consistent results were shown in the present study, indicating that EGFR or PI3K inhibitor combined with cisplatin may synergistically enhance the cytotoxicity of lung cancer cells, where cIAP2 is induced by E6 via the EGFR/PI3K/AKT cascade (Fig. 3C). However, the chemotherapeutic response enhanced by EGFR inhibitor plus cisplatin-based chemotherapy in cancer patients has failed (39), showing that a different molecular pathway may be responsible for the resistance to ...

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 …

Akt / ERK Inhibitor ONC201 in Treating Patients with Neuroendocrine Tumors That Are Locally Advanced, Metastatic, Recurrent, Refractory, or Cannot Be Removed by Surgery - NCT03034200

Principal Investigator：TODA Genji, Project Period (FY)：2001 - 2002, Research Category：Grant-in-Aid for Scientific Research (C), Section：一般, Research Field：Circulatory organs internal medicine

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Alternative Name. AKT3; v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma); RAC-gamma serine/threonine-protein kinase; PKBG; PRKBG; RAC gamma; PKB gamma; RAC-gamma serine/threonine protein kinase; STK-2; PKB-GAMMA; RAC-gamma; RAC-PK-gamma. ...

14-3-3 theta/tau (Ser232), 14-3-3 zeta (Ser58), 14-3-3 zeta/delta (Thr232), AKT (Ser473), AKT (Thr308), AKT (Tyr326), AKT1 (Ser124), AKT1 (Ser246), AKT1 (Thr450), AKT1 (Thr72), AKT1 (Tyr474), AKT1S1 (Thr246), AKT2 (Ser474), BAD (Ser112), BAD (Ser134), BAD (Ser136), BAD (Ser155), BAD (Ser91/128), BCL-2 (Ser70), BCL-2 (Ser87), BCL-2 (Thr56), BCL-2 (Thr69), BIM (Ser69/65), Cyclin D1 (Thr286), eNOS (Ser1177), eNOS (Ser615), eNOS (Thr495), FAK (Ser910), FAK (Tyr397), FAK (Tyr407), FAK (Tyr576), FAK (Tyr861), FAK (Tyr925), FKHR (Ser256), FKHR (Ser319), FOXO1/3/4-PAN (Thr24/32), FOXO1A (Ser329), FOXO1A/3A (Ser322/325), Gab1 (Tyr627), Gab1 (Tyr659), Gab2 (Tyr643), GABA-RB (Ser434), GSK3a-b (Tyr216/279), GSK3a (Ser21), GSK3b (Ser9), IKKa (Thr23), IKKa/b (Ser180/181), IRS-1 (Ser1101), IRS-1 (Ser307), IRS-1 (Ser312), IRS-1 (Ser323), IRS-1 (Ser612), IRS-1 (Ser636), IRS-1 (Ser639), IRS-1 (Ser794), JAK1 (Tyr1022), LYN (Tyr507), mTOR (Ser2448), mTOR (Ser2481), mTOR (Thr2446), MYT1, p21Cip1 (Thr145), p27Kip1 ...

AKT3 - AKT3 (untagged)-Human v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, gamma) (AKT3), transcript variant 1 available for purchase from OriGene - Your Gene Company.

2 3 4 eight 24 24C Hours soon after anti-CD3 Hours after anti-CD3 B Total Akt pAkt No anti-CD3 anti-CD3 No SPDB cost TU-100 Ginger GinsengJapanese Drug Pepper

USE OF ERBB4 AS A PROGNOSTIC AND THERAPEUTIC MARKER FOR MELANOMA - It is disclosed herein that members of the protein tyrosine kinase (PTK) family are highly mutated in patients with melanoma. Described herein are novel somatic mutations in the ERBB4 gene that result in increased kinase activity, transformation ability and anchorage-independent growth. These ERBB4 mutations contribute to the tumorogenicity of melanoma. Thus, provided herein is a method of predicting the prognosis of a patient with melanoma by detecting the presence or absence of a mutation in the ERBB4 gene. In some examples, the ERBB4 mutation is selected from G949A, G1354A, G1624A, C1630T, G1687A, G2506A and G2614A (numbering based on SEQ ID NO: 1). Also provided are methods of selecting a patient as a candidate for treatment with an ERBB4 and/or PI3K/AKT pathway inhibitor, and a method of identifying a therapeutic agent for the treatment of a subject diagnosed with melanoma. Oligonucleotides that specifically hybridize with ...

Introduction Weve shown previously that overexpression of constitutively dynamic Akt or activation of Akt due to constitutively dynamic Ras or individual epidermal development aspect receptor-2 (HER2) confers in breast cancers cells level of resistance to chemotherapy or radiotherapy. on phosphoinositide 3-kinase (PI3-K). An elevated baseline degree of Akt was within MCF7 cells treated with ionizing rays also. The cellular replies to doxorubicin-induced Akt phosphorylation had been potentiated following the appearance of Akt upstream activators including HER2, HER3 and focal adhesion kinase. Bottom line Used as well as our latest released outcomes displaying that constitutive Akt mediates level of resistance to radiotherapy or chemotherapy, our 443776-49-6 IC50 443776-49-6 IC50 present data claim that the doxorubicin-induced phosphorylation and activation of Akt might reveal a cellular protective mechanism of tumor cells to get over doxorubicin-induced cytotoxic results, which further works ...

AKT3 - AKT3 (untagged) - Homo sapiens v-akt murine thymoma viral oncogene homolog 3 (AKT3), transcript variant 3 available for purchase from OriGene - Your Gene Company.

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AKT1 overexpression lysate, 0.1 mg. Transient overexpression lysate of v-akt murine thymoma viral oncogene homolog 1 (AKT1), transcript variant 2

The multi-faceted roles of the PI3K-AKT pathway in melanoma. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.

Homo sapiens v-akt murine thymoma viral oncogene homolog 1 (AKT1), transcript variant 2, mRNA. (H00000207-R01V) - Products - Abnova

AKT (phospho Ser473) antibody (v-akt murine thymoma viral oncogene homolog 1) for IHC-P, IP, WB. Anti-AKT (phospho Ser473) pAb (GTX128414) is tested in Human, Mouse samples. 100% Ab-Assurance.

Akt (PKB, Rac kinase) is a 60kDa ser/thr kinase critical for controlling diverse cellular functions, including glucose metabolism, gene transcription, cell proliferation, and apoptosis. Akt phosphorylates a number of substrates including MBP, glycogen synthetase, PKA RII subunit, and histone H1. Akt is activated in res

p53 And Akt are critical players regulating tumorigenesis with opposite effects: whereas p53 transactivates target genes to exert its function as a tumor suppressor, Akt phosphorylates its substrates and transduces downstream survival signals. In addition, p53 and Akt negatively regulate each other …

Persistently hyperphosphorylated Akt contributes to human oncogenesis and resistance to therapy. Triciribine (TCN) phosphate (TCN-P), the active metabolite of the Akt phosphorylation inhibitor TCN, is in clinical trials, but the mechanism by which TCN-P inhibits Akt phosphorylation is unknown. Here we show that in vitro, TCN-P inhibits neither Akt activity nor the phosphorylation of Akt S473 and T308 by mammalian target of rapamycin or phosphoinositide-dependent kinase 1. However, in intact cells, TCN inhibits EGF-stimulated Akt recruitment to the plasma membrane and phosphorylation of Akt. Surface plasmon resonance shows that TCN, but not TCN, binds Akt-derived pleckstrin homology (PH) domain (K(D) 690 nM). Furthermore, nuclear magnetic resonance spectroscopy shows that TCN-P, but not TCN, binds to the PH domain in the vicinity of the PIP3-binding pocket. Finally, constitutively active Akt mutants, Akt1-T308D/S473D and myr-Akt1, but not the transforming mutant Akt1-E17K, are resistant to TCN ...

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane. AKT can have a number of downstream effects such as activating CREB, inhibiting p27, localizing FOXO in the cytoplasm, activating PtdIns-3ps, and activating mTOR which can affect transcription of p70 or 4EBP1. There are many known factors that enhance the PI3K/AKT pathway including EGF, shh, IGF-1, insulin, and CaM. The pathway is antagonized by various factors including PTEN, GSK3B, and HB9. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. This pathway is necessary, however, to promote growth and proliferation over differentiation of adult stem cells, neural stem cells specifically. It is the difficulty in finding an appropriate amount of proliferation versus ...

The model shows some of the prominent aspects of metabolism in proliferating cells, including glycolysis; lactate production; the use of TCA cycle intermediates as macromolecular precursors; and the biosynthesis of proteins, nucleotides, and lipids. The PI3K/Akt/mTOR pathway, HIF-1α, and Myc participate in various facets of this metabolic phenotype. The binding of a growth factor (GF) to its surface receptor brings about activation of PI3K and the serine/threonine kinases Akt and mTOR (top left). Constitutive activation of the pathway can occur in tumors due to mutation of the tumor suppressors PTEN, TSC1, and TSC2, or by other mechanisms (see text). Metabolic effects of the PI3K/Akt/mTOR pathway include enhanced uptake of glucose and essential amino acids and protein translation. The transcription factor HIF-1α (bottom) is involved in determining the manner in which cells utilize glucose carbon. Translation of HIF-1α is enhanced during growth-factor stimulation of the PI3K/Akt/mTOR pathway. ...

FERREIRA, MGPA et al. The importance of the PI3K/AKT/mTOR signaling pathway in canine neoplasms: Literature review. Arch. med. vet. [online]. 2016, vol.48, n.2, pp.139-143. ISSN 0301-732X. http://dx.doi.org/10.4067/S0301-732X2016000200002.. The PI3K/AKT/mTOR pathway is related to proliferation, protein synthesis, survival, angiogenesis, apoptosis, and cell motility. Genetic alterations in either activation of oncogenes or inactivation of tumor suppressor make it the second most altered pathway in neoplastic processes. The PI3K/AKT/mTOR pathway is currently considered an attractive target for the development of anti-tumor molecules. Specific inhibitors of this pathway are under development, and those already recognized are being tested in clinical trials, representing a promising approach for the treatment of cancer patients. It is believed that, as this pathway is involved in the development of many human cancers, its activation may also be related to the development of various canine neoplasms. ...

Akt phosphorylation by GDF-15 in endothelial cells. GDF-15 induced Akt phosphorylation at Ser437 in human pulmonary microvascular endothelial cells (HPMEC). The

Aberrant activation of the intracellular PI3K-AKT-mTOR signaling pathway, which regulates critical processes such as cell cycle and survival, is one of the most common occurrences in human cancers and has been the focus of targeted therapy development. However, inhibitors targeting PI3K, AKT, or mTOR have shown limited clinical benefit. To identify new regulators of the PI3K-AKT pathway, Wheeler and colleagues screened 7,450 shRNAs for kinases or GTPases that affect AKT phosphorylation at serine 473 (S473), and identified 29 genes that had not been previously implicated in PI3K-AKT signaling, as well as genes known to regulate AKT phosphorylation. Of the 29 genes, the most-represented functional group was the RAB GTPases, which regulate endomembrane trafficking. Knockdown of RAB35, one of the five RAB GTPases identified in the screen, in multiple cell lines resulted in decreased AKT phosphorylation at S473 as well as diminished phosphorylation of phosphoinositide-dependent kinase 1 (PDK1) and ...

Title:A Marine-based Meriolin (3-Pyrimidinylazaindole) Derivative (4ab) Targets PI3K/AKT /mTOR Pathway Inducing Cell Cycle Arrest and Apoptosis in Molt-4 Cells VOLUME: 6 ISSUE: 1. Author(s):Gousia Chashoo*, Umed Singh, Parvinder P. Singh, Dilip M. Mondhe and Ram A. Vishwakarma. Affiliation:Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Academy of Scientific and Innovative Research, Canal Road, Jammu, Jammu & Kashmir-180001, Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Academy of Scientific and Innovative Research, Canal Road, Jammu, Jammu & Kashmir-180001, Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Academy of Scientific and Innovative Research, Canal Road, Jammu, Jammu & Kashmir-180001, Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Academy of Scientific and Innovative ...

Catalpol induces cell activity to promote axonal regeneration via the PI3K/AKT/mTOR pathway in vivo and in vitro stroke model

Protein target information for Chain A, 3-phosphoinositide-dependent protein kinase 1 (human). Find diseases associated with this biological target and compounds tested against it in bioassay experiments.

Protein target information for Chain A, 3-phosphoinositide-dependent protein kinase 1 (human). Find diseases associated with this biological target and compounds tested against it in bioassay experiments.

TY - JOUR. T1 - Contribution of the PI 3-kinase/Akt survival pathway toward osmotic preconditioning. AU - Pastukh, Viktor. AU - Ricci, Craig. AU - Solodushko, Viktoriya. AU - Mozaffari, Mahmood. AU - Schaffer, Stephen W.. PY - 2005/1/1. Y1 - 2005/1/1. N2 - Osmolytes are rapidly lost from the ischemic heart, an effect thought to benefit the heart by reducing the osmotic load. However, the observation that chronic lowering of one of the prominent osmolytes, taurine, is more beneficial to the ischemic heart than acute taurine loss suggests that osmotic stress may benefit the ischemic heart through multiple mechanisms. The present study examines the possibility that chronic osmotic stress preconditions the heart in part by stimulating a cardioprotective, osmotic-linked signaling pathway. Hyperosmotic stress was produced by treating rat neonatal cardiomyocytes during the pre-hypoxic period with either the taurine depleting agent, ß-alanine (5 mM), or with medium containing 25 mM mannitol. The cells ...

The ser-thr Akt plays a crucial role in the regulation of cell success cell growth and proliferation aswell as energy metabolism and it is dysregulated in lots of cancers. of IKKα in managing Akt activity and whether this might involve mTORC2. The tests display that IKKα affiliates with mTORC2 in a number of cancers cells in a way reliant on PI3K/Akt activity which IKKα favorably promotes Akt phosphorylation R935788 at Ser473 with Thr308. Furthermore IKKα enhances mTORC2 kinase activity aimed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3β however not additional Akt-associated targets such as for example TSC2 and PRAS40 indicating the lifestyle of multiple AFX1 systems of Akt activation in cells. In addition loss of IKKα suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKKα serves as a feedforward R935788 regulator of mTORC2 and that IKKα could serve as a key therapeutic target to block mTORC2 and Akt ...

TY - JOUR. T1 - Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. AU - Dobson, Tara H.W.. AU - Tao, Rong Hua. AU - Swaminathan, Jyothishmathi. AU - Maegawa, Shinji. AU - Shaik, Shavali. AU - Bravo-Alegria, Javiera. AU - Sharma, Ajay. AU - Kennis, Bridget. AU - Yang, Yanwen. AU - Callegari, Keri. AU - Haltom, Amanda R.. AU - Taylor, Pete. AU - Kogiso, Mari. AU - Qi, Lin. AU - Khatua, Soumen. AU - Goldman, Stewart. AU - Lulla, Rishi R.. AU - Fangusaro, Jason. AU - MacDonald, Tobey J.. AU - Li, Xiao Nan. AU - Hawkins, Cynthia. AU - Rajaram, Veena. AU - Gopalakrishnan, Vidya. PY - 2019/1/22. Y1 - 2019/1/22. N2 - In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH- (children 3 to 16 years) and SHH- (infants) subgroups. Neuronal maturation is greater in SHH- than ...

In this study, we have found that Fstl1 transcript and protein are upregulated in the myocardium after Akt1 transgene activation. Our studies have also revealed that Fstl1 is a secreted protein and that its overexpression will promote Akt and ERK1/2 signaling in cardiac myocytes and protect cardiac myocytes from hypoxia/reoxygenation-induced apoptosis through activation of these pathways. Conversely, siRNA-mediated knockdown of Fstl1 led to an increase in the frequency of stress-induced apoptosis, and this was associated with a reduction in basal Akt phosphorylation. Fstl1 expression was also upregulated in the heart after pathological stimuli including pressure overload, ischemia/reperfusion, and permanent LAD ligation. Finally, the systemic delivery of Fstl1 protected myocardium from ischemia/reperfusion injury, which was accompanied with a reduction in apoptosis.. A number of lines of evidence suggest that Fstl1 is secreted from cardiac myocytes. Cardiac myocyte cultures display ...

Many studies have shown that TRAIL is a potent apoptosis inducer in malignant cells, whereas its role in normal cell physiology is much less well understood.1 We have demonstrated here that both aortic endothelial cells and HUVECs exhibit a similar pattern of surface TRAIL-R expression. Moreover, in vascular endothelial cells, TRAIL stimulates the phosphorylation of the serine/threonine kinase Akt in a manner dependent on PI3K activation.14 The ability of TRAIL to activate the antiapoptotic PI3K/Akt pathway in endothelial cells is a completely new and unexpected finding, also in consideration of the large number of studies underlining the proapoptotic activity of TRAIL, at least in malignant cells.1,4,5 It should be underlined that the PI3K/Akt pathway is of central importance in endothelial cell biology, conferring survival to endothelial cells in response to angiogenic cytokine stimulation, fluid shear stress, and matrix attachment signals. This pathway is essential also for endothelial cell ...

The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mutations in this gene have been associated with the Proteus syndrome. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2011] Product Name ...

Our results show that eNOS activation by TNF-α occurs by phosphorylation of Ser 1179 and requires activation of both N-SMase and Akt. The data indicate that the involvement of the two enzymes is sequential, because inhibition of N-SMase abolished the phosphorylation of Akt induced by TNF-α. Changes in [Ca2+]c seem to play no major role in this signaling pathway. These findings establish a link between N-SMase and eNOS and indicate that activation of eNOS by TNF-α occurs through a pathway different from those activated by any other stimulus described so far. Indeed a variety of stimuli as diverse as shear stress, estrogen, vascular endothelial growth factor, insulin, corticosteroids, sphingosine 1-phosphate, lysophosphatidic acid, and possibly bradykinin have been shown to activate eNOS through a PI3K/Akt-dependent pathway (Fulton et al., 1999; Dimmeler et al., 1999;Haynes et al., 2000; Fleming et al., 2001; Harris et al., 2001;Igarashi et al., 2001; Montagnani et al., 2001; Morales-Ruiz et ...

Akt can be an intracellular signalling pathway that acts as an important hyperlink between cell surface area receptors and cellular procedures including proliferation, advancement and success. MDA-MB-468 cells. Treatment with either the phosphoinositide-3-kinase inhibitor, type:entrez-nucleotide,attrs:text message:LY294002″,term_id:1257998346″,term_text message:LY294002″LY294002 and pan-mTOR inhibitor, AZD8055 however, not pan-Akt inhibitor MK2206 improved uridine-5-diphosphate-hexose cell content material that was suppressed by co-treatment with glycogen synthase kinase 3 inhibitor SB216763. This shows that there can be an Akt-independent hyperlink between phosphoinositol-3-kinase and glycogen synthase kinase3 and demonstrates the potential of 31P-NMR to Y-33075 Y-33075 probe intracellular signalling pathways. The PI3K/Akt/mTOR signalling pathway is definitely activated by many tyrosine kinase receptors like the insulin receptor as well as the human being epithelial ...

Earlier studies from our laboratory indicated that lowering the expression of PDK1 has a pronounced effect on tumorigenesis of PTEN+/− mice (Bayascas et al., 2005). Reduction in levels of PDK1 expression is likely to impact on the activity of multiple downstream targets of PDK1. However, the only major signalling defect we observed in the PDK1K465E/K465EPTEN+/− mice was a moderate reduction of Akt T308 phosphorylation, which reduces Akt isoform activity. All other AGC kinases we have studied, including S6K1 and SGK activity (as judged by phosphorylation of NDRG1), are not affected in the tumours that develop in the PDK1K465E/K465EPTEN+/− mice. This indicates that a moderate reduction in Akt isoform activity is sufficient to delay tumour onset and development. The mechanism by which reduction in Akt activity delays tumour onset and development requires further investigation because phosphorylation of the Akt substrates we have investigated is not markedly inhibited in tumours derived from ...

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene. It is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533. FOXO4 is a member of the forkhead family transcription factors O subclass, which is characterized by a winged helix domain used for DNA binding. There are 4 members of the FOXO family, including FOXO1, FOXO3, and FOXO6. Their activity is modified by many post translational activities, such as phosphorylation, ubiquitination, and acetylation. Depending on this modified state, FOXO4 binding affinity for DNA is altered, allowing for FOXO4 to regulate many cellular pathways including oxidative stress signaling, longevity, insulin signaling, cell cycle progression, and apoptosis. Two of the main upstream regulators of FOXO4 activity are phosphoinositide 3- kinase (PI3K) and serine/threonine kinase AKT/PKB. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of ...

mTORC1 is a downstream target of the PI3K/Akt pathway, but can be engaged by alternative signaling pathways as well. Therefore, to determine whether fulvestrant-induced ErbB3 signaling promotes mTOR activity through the PI3K pathway, we used small molecular weight kinase inhibitors to block precise steps in the PI3K/mTOR signal transduction cascade for the final 2 hours of culture. The Akt inhibitor MK2206 (1 μM) and the PI3K inhibitor BKM120 (0.5 μM) blocked fulvestrant-induced P-S6, suggesting that mTOR is activated downstream of PI3K/Akt in fulvestrant-treated cells (Figure 6A). The MEK inhibitor U0126 did not affect P-S6 upregulation in response to fulvestrant. Inhibition of PDK, a PI3K-activated kinase that phosphorylates Akt at T308, impaired fulvestrant-induced P-S6 (Supplemental Figure 16), while inhibition of serum glucose kinase (SGK), another PI3K-activated kinase, appeared to increase S6 phosphorylation under basal conditions and did not affect P-S6 levels in fulvestrant-treated ...

Li, Y., Hu, S-Q., & Han, Y. (2015). Preventing H2O2-induced toxicity in primary cerebellar granule neurons via activating the PI3-K/Akt/GSK3ß pathway by kukoamine from Lycii Cortex. Journal of Functional Foods, 17, 709 - 721 ...

Mechanisms of abnormal protein phosphorylation that regulate cell invasion and metastasis in pancreatic cancer remain obscure. In this study, we used high-throughput phosphorylation array to test two pancreatic cancer cell lines (PC-1 cells with a low, and PC-1.0 cells with a high potential for invasion and metastasis). We noted that a total of 57 proteins revealed a differential expression (fold change ≥ 2.0). Six candidate proteins were further validated by western blot with results found to be accordance with the array. Of 57 proteins, 32 up-regulated proteins (e.g. CaMK1-α and P90RSK) were mainly involved in ErbB and neurotrophin signaling pathways as determined using DAVID software, while 25 down-regulated proteins (e.g. BID and BRCA1) were closely involved in apoptosis and p53 signaling pathways. Moreover, four proteins (AKT1, Chk2, p53 and P70S6K) with different phosphorylation sites were found, not only among up-regulated, but also among down-regulated proteins. Importantly, specific ...

The AKT-GSK3β-eIF2Bε signaling module plays a key role in promoting axon regeneration in the adult mammalian central nervous system.

‌A new, pre-clinical study by researchers at Virginia Commonwealth University Massey Cancer Center suggests that a novel drug combination could lead to profound leukemia cell death by disrupting the function of two major pro-survival proteins. The effectiveness of the therapy lies in its ability to target a pro-survival cell signaling pathway known as PI3K/AKT/mTOR, upon which the leukemia cells have become dependent.. In the study, published in the journal Cancer Research, researchers combined the drug ABT-737 with another agent BEZ235. ABT-737 targets proteins known as B-cell lymphoma 2 (Bcl-2) and Bcl-xL, which prevent apoptosis, a form of cell suicide, in cancer cells. BEZ235 directly inhibits the PI3K/AKT/mTOR pathway, and as a result, reduces the expression of another anti-apoptotic protein known as Mcl-1, which is not targeted by ABT-737. Among their many functions, signaling pathways regulate biological processes required for cellular survival. The PI3K/AKT/mTOR pathway helps keep ...

GIRDers of actIN filament (Girdin) belongs to a family of proteins characterized by the presence of a coiled-coil domain. Girdin is an actin-binding protein that is activated by the serine/threonine kinase Akt. Girdin is a key modulator of the AKT-mTOR signaling pathway that controls the timing of newborn neuron integration during adult neurogenesis, including correct neuron positioning, dendritic development, and synapse formation. It also enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent activation of Akt by growth factor receptor tyrosine kinases and G protein-coupled receptors (GPCRs). Elevated levels of Girdin expression are associated with cancer metastasis. Girdin is also known as coiled-coil domain containing 88A (CCDC88A), G alpha-interacting vesicle-associated protein, Hook-related protein 1, Akt-phosphorylation enhancer (APE), GIV, GRDN, HkRP1, and KIAA1212.. ...

GIRDers of actIN filament (Girdin) belongs to a family of proteins characterized by the presence of a coiled-coil domain. Girdin is an actin-binding protein that is activated by the serine/threonine kinase Akt. Girdin is a key modulator of the AKT-mTOR signaling pathway that controls the timing of newborn neuron integration during adult neurogenesis, including correct neuron positioning, dendritic development, and synapse formation. It also enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent activation of Akt by growth factor receptor tyrosine kinases and G protein-coupled receptors (GPCRs). Elevated levels of Girdin expression are associated with cancer metastasis. Girdin is also known as coiled-coil domain containing 88A (CCDC88A), G alpha-interacting vesicle-associated protein, Hook-related protein 1, Akt-phosphorylation enhancer (APE), GIV, GRDN, HkRP1, and KIAA1212.. ...

TY - JOUR. T1 - AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling. AU - Riemenschneider, Markus J.. AU - Betensky, Rebecca A.. AU - Pasedag, Saskia M.. AU - Louis, David N.. PY - 2006/6/1. Y1 - 2006/6/1. N2 - Aberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within ...

Clone REA134 recognizes AKT1, which is also known as protein kinase Bα. AKT1 is a serine/threonine protein kinase, belonging to the AKT family of kinases and like each AKT family member, contains an N-terminal pleckstrin homology (PH) domain, a central kinase domain, and a carboxyl-terminal regulatory domain with a hydrophobic motif (HM). Activation of AKT1 is achieved via phosphorylation at multiple sites, which take place in response to engagement of receptors such as platelet derived growth factor receptor (PDGF-R). Activated AKT1 further phosphorylates and alters the activity of several downstream substrates allowing AKT1 to play a vital role in various biological processes such as cell growth, survival, migration, and proliferation. Additional information: Clone REA134 displays negligible binding to Fc receptors. - Belgique

The study of eukaryotic initiation factor 4E (eIF4E) is a key focus in cancer research due to its role in controlling the translation of tumour-associated proteins, that drive an aggressive migratory phenotype. eIF4E is a limiting component of the eIF4F complex which is a critical determinant for the translation of mRNAs. Mitogenactivated protein kinase interacting protein kinases (MNK1/2) phosphorylate eIF4E on Ser209, promoting the expression of oncogenic proteins, whereas mTORC1 phosphorylates and de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Here we show that inhibiting these pathways simultaneously effectively slows the rate of cell migration in breast cancer cells. However, a molecular hybridisation approach using novel, cleavable dual MNK1/2 and PI3K/mTOR inhibiting hybrid agents was less effective at slowing cell migration.. ...

Cell-released microvesicles (MVs) represent a novel way of cell-to-cell communication. Previous evidence indicates that endothelial progenitor cells (EPCs)-derived MVs can modulate endothelial cell survival and proliferation. In this study, we evaluated whether EPC-MVs protect cardiomyocytes (CMs) against angiotensin II (Ang II)-induced hypertrophy and apoptosis. The H9c2 CMs were exposed to Ang II in the presence or absence of EPC-MVs. Cell viability, apoptosis, surface area and β-myosin heavy chain (β-MHC) expression were analyzed. Meanwhile, reactive oxygen species (ROS), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS), and their phosphorylated proteins (p-Akt, p-eNOS) were measured. Phosphatidylinositol-3-kinase (PI3K) and NOS inhibitors were used for pathway verification. The role of MV-carried RNAs in mediating these effects was also explored. Results showed 1) EPC-MVs were able to protect CMs against Ang II-induced changes in cell viability, apoptosis, surface area, β

TY - JOUR. T1 - TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. AU - Cooper, Jonathan M.. AU - Ou, Yi Hung. AU - McMillan, Elizabeth A.. AU - Vaden, Rachel M.. AU - Zaman, Aubhishek. AU - Bodemann, Brian O.. AU - Makkar, Gurbani. AU - Posner, Bruce A.. AU - White, Michael A.. PY - 2017/9/15. Y1 - 2017/9/15. N2 - Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action ...

The present invention is to provide a polypeptide specifically inhibiting the activity of Akt (Protein Kinase B), the DNA thereof, the antibody thereof, an inhibitor of Akt activity or an antitumor agent, and the like. The polypeptide comprises polypeptides (SEQ ID NO: 1, 3, 5, 7, and 9 of the sequence listing) that contain an amino acid sequence corresponding to any of the position of amino acid residue 10-24 of human TCL1, amino acid residue 8-22 of human TCL1B, amino acid residue 5-19 of human MTCP1, and amino acid residue 9-24 of mouse or rat TCL1; and the derivatives. Further, the present invention includes DNA encording the polypeptide (SEQ ID NO: 2, 4, 6, 8 or 10 of the sequence listing), and the antibodies specifically binding to the polypeptides. The polypeptide of the present invention can be used for an inhibitor of Akt activity, an antitumor agent, or the like.

Effect of microRNA-21 on PTEN/AKT/FOXO3a signal transduction pathway, Ying Han, Wen-Yan Xie, Chang-Sheng Xu, Hua-Jun Wang, XianE Peng

Akt is activated downstream of the growth factor receptors and oncogenes implicated in human cancer and plays a critical role in normal development, as well as in tumor pathogenesis, via effects on metabolism, survival, and proliferation. The role of Akt in cell migration and metastases is less clear because of conflicting studies suggesting either positive or negative regulatory roles (Shaw et al., 1997; Park et al., 2001). Previous studies have largely relied on overexpression strategies in cancer cell lines or pharmacological inhibitors of PI 3-kinase activity, which would inhibit activity of all Akt isoforms. We describe studies that reveal isoform-specific roles for endogenous Akt1 and -2 in both positive and negative regulation of processes downstream of growth factor receptors and provide insights into mechanisms that may be partly responsible for those conflicting conclusions. In addition, we provide evidence for the importance of Akt1 in a cross-regulatory control circuit between the PI ...

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Molecular mechanism of microRNA-93 in suppressing the cell proliferation of cervical cancer by adjusting the EGFR/AKT signal pathway, Xue Dong, Yan Wang

In addition, overexpression led to increased c-FLIPL Ht hypoxia-inducible factor 1 An overexpression of HIF-1 can up-regulation of genes that lead to global Ver Changes in cell proliferation, metastasis and invasion. In addition, overexpression of c-FLIP accelerated progression to Androgenunabh Dependence through the inhibition of apoptosis in LNCaP prostate tumors in mice Nacktm Implanted. Gathering information clearly shows that c-FLIP plays a role Middle finger in the development of resistance to death ligands and chemotherapeutic agents. Park et al. reported that MEK1 / 2 inhibitors interact synergistically with heat shock protein 90 inhibitor, hepatoma and pancreatic cancer in order to t th geldanamycins. Treatment of cells with MEK1 / 2 inhibitors and 17AAG reduced expression of c-flips was that the loss of MEK1 / 2 and AKT function is connected. In addition, the overexpression of c led flips or inhibition of caspase-8 abolished the Zellabt Tion by MEK1 / 2 inhibitors and 17AAG. ...

LncRNA TDRG1 Promotes Proliferation, Invasion and Epithelial-Mesenchymal Transformation of Osteosarcoma Through PI3K/AKT Signal Pathway

reacts with Akt when phosphorylated at Ser473; also reacts with Akt2 and Akt3 when phosphorylated at corresponding residues. Does not recognize Akt phosphorylated at other sites, nor does it recognize phosphorylated forms of related kinases such as PKC or p70 S6 ...

Phosphorylation is a key reaction where a phospho group (PO4) is added to protein via enzymatic processes. This allows for protein modification that is central in cell signaling, cellular regulation, cell adhesion, and many more important cellular processes. Phospho protein modification predominantly occurs on amino groups: serine, threonine, and tyrosine. These modified groups on proteins are the focus of post translational modifications. Assay Biotechnology is proud to provide antibodies that are specific for these phosphorylated proteins. ...

Reactome is pathway database which provides intuitive bioinformatics tools for the visualisation, interpretation and analysis of pathway knowledge.

Mono- and Stereopictres of 5.0 Angstrom coordination sphere of Bromine atom in PDB 2uzw: Pka Structures Of Indazole-Pyridine Series of Akt Inhibitors