Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

System ASC amino acid transporter-2 (ASCT2) was previously demonstrated to be essential for human hepatoma cell growth and survival, as its silencing via inducible antisense RNA expression results in complete apoptosis within 48 h by a mechanism that transcends its role in amino acid delivery. To gain mechanistic insights into the reliance of cancerous liver cells on ASCT2, the aim of this study was to determine the early consequences of its silencing on the growth and survival signaling that presage apoptosis. Induced antisense ASCT2 RNA in SK-Hep1 cells led to >90% suppression of ASCT2 mRNA by 6 h and inhibition of mammalian target-of-rapamycin (mTOR)/raptor (mTOR complex-1; mTORC1) signaling by 8 h, as manifested by diminished p70 ribosomal protein S6 kinase-1 and eukaryotic initiation factor-4E (eIF4E) binding protein-1 phosphorylation, while protein synthesis rates declined by nearly 50% despite no measurable decreases in the cap binding protein eIF4G or cellular ribosomal protein content. Depressed mTORC1 signaling occurred before detectable reduction in ASCT2 activity but coincided with a 30% decline in total cellular ASCT2 protein. By 12 h after ASCT2 silencing, further decrements were observed in protein synthesis rates and ASCT2 protein and activity, each by approximately 50%, while signaling from mTOR/rictor (mTOR complex-2; mTORC2) was stimulated as indexed by enhanced phosphorylation of the Akt/PKB kinase on serine-473 and of its proapoptotic substrate Bad on serine-136. These results suggest that ASCT2 silencing inhibits mTORC1 signaling to the translational machinery followed by an mTORC2-initiated survival response, establishing a link between amino acid transporter expression and mTOR function.
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PMID:ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells. 1732

In the present study the role of Akt/PKB (protein kinase B) in PIF- (proteolysis-inducing factor) induced protein degradation has been investigated in murine myotubes. PIF induced transient phosphorylation of Akt at Ser(473) within 30 min, which was attenuated by the PI3K (phosphoinositide 3-kinase) inhibitor LY294002 and the tyrosine kinase inhibitor genistein. Protein degradation was attenuated in myotubes expressing a dominant-negative mutant of Akt (termed DNAkt), compared with the wild-type variant, whereas it was enhanced in myotubes containing a constitutively active Akt construct (termed MyrAkt). A similar effect was observed on the induction of the ubiquitin-proteasome pathway. Phosphorylation of Akt has been linked to up-regulation of the ubiquitin-proteasome pathway through activation of NF-kappaB (nuclear factor kappaB) in a PI3K-dependent process. Protein degradation was attenuated by rapamycin, a specific inhibitor of mTOR (mammalian target of rapamycin), when added before, or up to 30 min after, addition of PIF. PIF induced transient phosphorylation of mTOR and the 70 kDa ribosomal protein S6 kinase. These results suggest that transient activation of Akt results in an increased protein degradation through activation of NF-kappaB and that this also allows for a specific synthesis of proteasome subunits.
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PMID:Involvement of phosphoinositide 3-kinase and Akt in the induction of muscle protein degradation by proteolysis-inducing factor. 1796 Nov 25

Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction, but its specific pathomechanism remains unknown. Thus, we performed a systematic expression profiling of genes by microarray analysis in the acute phase and after functional recovery. We studied 3 female patients presenting with TTC. Complementary RNA was isolated from left ventricular biopsies taken in the acute phase (group A) and after functional recovery (group B). It was profiled for gene expression using cDNA microarrays. Functionally related genes were determined with the Gene Set Enrichment Analysis (GSEA) bioinformatic tool. Validation of selected genes was performed by means of real-time PCR and immunohistochemistry. In group A, different functional gene sets, such as Nrf2-induced genes, triggered by oxidative stress, and protein biosynthesis were significantly overrepresented among the upregulated targets. Increased transcription of GPX1, CAT, RPS6, and eIF4E was confirmed by RT-PCR. The targets of the Akt/PKB signaling showed significant upregulation in both groups. Immunohistochemistry showed that the downstream targets NF-kappaB and BcL-X(L) are upregulated and activated. Gene sets involved in energy metabolism (oxidative phosphorylation, mitochondrial genes) showed no differences in group A but were overexpressed in group B. This study demonstrated a significant contribution of oxidative stress to the pathomechanism of TTC; it is possibly triggered by excess catecholamine. Increased protein biosynthesis and an activated cell survival cascade can be interpreted as potential compensatory mechanisms. After functional recovery, processes involved in energy metabolism play a pivotal role, thereby potentially contributing to the normalization of contractile function.
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PMID:Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy: insight into a new cardiac entity. 1805 41

We investigated the effect of resistance exercise and feeding on the activation of signaling proteins involved in translation initiation. Nine young men (23.7+/-0.41 yr; BMI=25.5+/-1.0 kg/m2; means+/-SE) were tested twice after they performed a strenuous bout of unilateral resistance exercise, such that their contralateral leg acted as a nonexercised comparator, in either the fasted and fed [1,000 kJ, each 90 min (3 doses): 10 g protein, 41 g carbohydrate, 4 g fat] states. Muscle biopsies were obtained 6 h postexercise from both legs, resulting in four experimental conditions: rest-fasted, rest-fed, exercise-fasted, and exercise-fed. Feeding increased PKB/Akt (Ser473) phosphorylation (P<0.05), while exercise increased the phosphorylation of Akt and the downstream 70 kDa S6 protein kinase (p70S6K1, Thr389) and ribosomal protein S6 (rpS6, Ser235/236, Ser240/244; all P<0.05). The combination of resistance exercise and feeding increased the phosphorylation of p70S6K1 (Thr389) and rpS6 (Ser240/244) above exercise alone (P<0.05). Exercise also reduced phosphorylation of the catalytic epsilon subunit of eukaryotic initiation factor 2B (eIF2Bepsilon, Ser540; P<0.05). Mammalian target of rapamycin (mTOR, Ser2448), glycogen synthase kinase-3beta (GSK-3beta, Ser9), and focal adhesion kinase (FAK, Tyr576/577) phosphorylation were unaffected by either feeding or resistance exercise (all P>0.14). In summary, feeding resulted in phosphorylation of Akt, while resistance exercise stimulated phosphorylation of Akt, p70S6K1, rpS6, and dephosphorylation eIF2Bepsilon with a synergistic effect of feeding and exercise on p70(S6K1) and its downstream target rpS6. We conclude that resistance exercise potentiates the effect of feeding on the phosphorylation and presumably activation of critical proteins involved in the regulation of muscle protein synthesis in young men.
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PMID:Resistance exercise decreases eIF2Bepsilon phosphorylation and potentiates the feeding-induced stimulation of p70S6K1 and rpS6 in young men. 1856 37

The mammalian target of rapamycin (mTOR) is a nutrient and ATP sensor suggested to play an important role in tumorigenesis, particularly in the setting of PTEN loss or activated Akt/PKB. Of mTOR's two known effectors, eIF4E has been implicated in tumorigenesis, whereas the role of S6 kinase (S6K1) in transformation is less understood. To assess the contribution of S6K1 to the transformed phenotype, we pharmacologically and genetically manipulated the mTOR-S6K pathway in glioma cells and monitored its effects on growth in soft agar, a hallmark of cellular transformation, and also assessed in vivo intracranial growth. Anchorage-independent growth by HRas(V12)-transformed human astrocytes as well as by U251 and U373 human glioma cells was inhibited by pharmacologic mTOR inhibition. Similarly, short hairpin RNA-mediated suppression of mTOR also reduced anchorage-independent growth of glioma cell lines. Expression of wild-type eIF4E in rapamycin-treated E6/E7/hTert/HRas(V12) and U373 cells failed to rescue colony formation, although expression of wild-type S6K1 or rapamycin-resistant S6K1 in rapamycin-treated U373 and U251 provided partial rescue. Consistent with the latter observation, small interfering RNA-mediated suppression of S6K1 in HRas(V12)-transformed human astrocytes, U251, and U373 cells resulted in a significant loss of anchorage-independent growth. Furthermore, we found that in vivo short hairpin RNA-mediated suppression of S6K1 in HRas(V12)-transformed human astrocytes reduced intracranial tumor size, in association with reduced tumor levels of phosphorylated ribosomal protein S6. These findings implicate the mTOR-S6K pathway as a critical mediator of glial cell transformation.
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PMID:S6K1 plays a key role in glial transformation. 1870 74

GLUT4 (glucose transporter 4) plays important roles in glucose homoeostasis in vivo. GLUT4 expression and function are diminished in diabetic human and animal subjects. The goal of the present study is to develop a cell-based assay for identifying negative regulators of GLUT4 translocation as potential targets for the treatment of Type 2 diabetes. Traditional GLUT4 translocation assays performed in differentiated myocytes or adipocytes are difficult to perform, particularly in HTS (high-throughput screening) mode. In the present study, we stably co-expressed c-Myc and eGFP [enhanced GFP (green fluorescent protein)] dual-tagged recombinant GLUT4 with recombinant IRS1 (insulin receptor substrate 1) in HEK-293 cells (human embryonic kidney cells) (HEK-293.IRS1.GLUT4 cells). Insulin treatment stimulated both glucose uptake and GLUT4 translocation in these cells. GLUT4 translocation is quantified by a TRF (time-resolved fluorescence) assay in a 96-well HTS format. TRF assays confirmed insulin-stimulated GLUT4 translocation, which can be inhibited by PI3K (phosphoinositide 3-kinase) or Akt [also called PKB (protein kinase B)] inhibitors. Treatment with palmitate increased IRS1 serine phosphorylation and reduced insulin-stimulated Akt phosphorylation and GLUT4 translocation, indicating insulin resistance. Knockdown of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and PTP1B (protein tyrosine phosphatase 1B) gene expression by siRNA (small interfering RNA) treatment significantly increased GLUT4 translocation only in cells treated with palmitate but not in untreated cells. Similar results were obtained on treatment with siRNA of JNK1 (c-Jun N-terminal kinase 1), S6K1 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1) and PKC(theta) (protein kinase C theta). In summary, we have established and validated a novel GLUT4 translocation assay that is optimal for identifying negative regulators of GLUT4 translocation. In combination with more physiologically relevant secondary assays in myotubes and adipocytes, this assay system can be used to identify potential novel therapeutic targets for the treatment of Type 2 diabetes.
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PMID:Development of a novel GLUT4 translocation assay for identifying potential novel therapeutic targets for insulin sensitization. 1903 54

Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC(50) of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G(1) arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide.
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PMID:Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. 1919 Jan 19

The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.
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PMID:Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. 1956 71

The rapamycin-insensitive companion of mammalian target of rapamycin (mTOR) (Rictor) is a key member of mTOR complex-2 (mTORC2), which phosphorylates the AGC kinases Akt/PKB, PKC and SGK1 at a C-terminal hydrophobic motif. We identified several novel sites on Rictor that are phosphorylated, including Thr1135, which is conserved across all vertebrates. Phosphorylation of this site on Rictor is stimulated by amino acids and growth factors through a rapamycin-sensitive signaling cascade. We demonstrate here that Rictor is a direct target of the ribosomal protein S6 kinase-1 (S6K1). Rictor phosphorylation at Thr1135 does not lead to major changes in mTORC2-kinase activity. However, phosphorylation of this site turns over rapidly and mediates 14-3-3 binding to Rictor and mTORC2, providing possibility for altered interactions of the complex. These findings reveal an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.
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PMID:Rictor is a novel target of p70 S6 kinase-1. 1993 11

Hispidulin, an active component from Artemisia vestita, a traditional Tibetan medicinal plant, has been shown to possess anti-inflammatory and anti-oxidative activities. However, the functional role of hispidulin on tumor growth and angiogenesis has not been elucidated. We found that hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when s.c. treated at a dosage of 20 mg/kg daily, and this effect was accompanied with a potent inhibition on angiogenesis. When examining the cytotoxicity of hispidulin on HUVECs and pancreatic cancer cells in vitro, we found that HUVECs were more susceptible to the treatment, suggesting angiogenesis might be the primary target of hispidulin. Our results further showed that hispidulin inhibited vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs in a dose-dependent manner. In ex vivo and in vivo angiogenesis assays, we showed that hispidulin suppressed VEGF-induced microvessel sprouting of rat aortic rings and corneal neovascularization in C57/BL6 mice. To understand the underlying molecular basis, we next examined the effects of hispidulin on different molecular components in treated HUVECs, and found that hispidulin suppressed the VEGF-triggered activation of VEGF receptor 2, PI3K, Akt, mTOR, and ribosomal protein S6 kinase, but had little effect on focal adhesion kinase or extracellular signal-regulated kinase at an effective concentration. Taken together, our results indicate that hispidulin targets the VEGF receptor 2-mediated PI3K/Akt/mTOR signaling pathway in endothelial cells, leading to the suppression of pancreatic tumor growth and angiogenesis.
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PMID:Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2-mediated PI3K/Akt/mTOR signaling pathway. 2108 51


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