Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the role of endogenous 70-kDa S6 kinase (p70(S6K)) in actin cytoskeletal organization and cell migration in Swiss 3T3 fibroblasts. Association of p70(S6K) with the actin cytoskeleton was demonstrated by cosedimentation of p70(S6K) with F-actin and by subcellular fractionation in which p70(S6K) activity was measured in the F-actin cytoskeletal fraction. Immunocytochemical studies showed that p70(S6K), Akt1, PDK1, and p85 phosphoinositide 3-kinase (PI 3-kinase) were localized to the actin arc, a caveolin-enriched cytoskeletal structure located at the leading edge of migrating cells. Using a phospho-specific antibody to mammalian target of rapamycin (mTOR), we find that activated mTOR is enriched at the actin arc, suggesting that activation of the p70(S6K) signaling pathway is important to cell migration. Using the actin arc to assess migration, epidermal growth factor (EGF) stimulation was found to induce actin arc formation, an effect that was blocked by rapamycin treatment. We show further that actin stress fibers may function to down-regulate p70(S6K). Fibronectin stimulated stress fiber formation in the absence of growth factors and caused an inactivation of p70(S6K). Conversely, cytochalasin D and the Rho kinase inhibitor Y-27632, both of which cause stress fiber disruption, increased p70(S6K) activity. These studies provide evidence that the p70(S6K) pathway is important for signaling at two F-actin microdomains in cells and regulates cell migration.
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PMID:Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. 1514 49

Adequate extravillous trophoblast (EVT) invasion is an essential step for placental formation. The aim of this study was to examine the possible role of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling in epidermal growth factor (EGF)-induced EVT migration and to determine if the 70 kDa ribosomal S6 kinase (p70S6K) is involved in this process. In this study, EGF significantly stimulated HTR8/SVneo cell migration and the phosphorylation of AKT, ERK1/2 and p70S6K in a concentration-dependent manner. The MAPK inhibitor U0126 decreased cell migration and ERK phosphorylation, but it did not influence p70S6K phosphorylation in response to EGF. In the presence of PI3K inhibitors (Wortmannin), EGF-stimulated trophoblast migration and phosphorylation of AKT and P70S6K (Thr(389) and Thr(421)/Ser(424)) were decreased, while EGF-induced ERK phosphorylation was not affected. Expression of an activated AKT (Myr-AKT2) increased basal phospho-p70S6K (Thr(389) and Thr(421)/Ser(424)) content, but failed to stimulate cell migration. However, it induced cell migration in the presence of EGF and Wortmannin, in which both AKT and MAPK pathways were activated. In addition, there was a concentration-dependent inhibition of cell migration and p70S6K phosphorylation (Thr(389) and Thr(421)/Ser(424)) in the presence of Rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR, a downstream of AKT). Taken together, our data suggest that EGF-induced trophoblast migration involves the coordinated regulation of both PI3K/AKT and MAPK signalling pathways. mTOR/p70S6K is important in PI3K- but not MAPK-mediated trophoblast migration in response to EGF.
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PMID:Both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signalling are required in epidermal growth factor-induced human trophoblast migration. 1523 5

We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by PKBa (protein kinase Ba), but not by SGK1 (serum- and glucocorticoid-induced kinase 1), and identified it as the cytoskeletal protein FLNc (filamin C). PKBa phosphorylated FLNc at Ser2213 in vitro, which lies in an insert not present in the FLNa and FLNb isoforms. Ser2213 became phosphorylated when C2C12 myoblasts were stimulated with insulin or epidermal growth factor, and phosphorylation was prevented by low concentrations of wortmannin, at which it is a relatively specific inhibitor of phosphoinositide 3-kinase. PD 184352 [an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade] and/or rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] had no effect. Insulin also induced the phosphorylation of FLNc at Ser2213 in cardiac muscle in vivo, but not in cardiac muscle that does not express PDK1 (3-phosphoinositide-dependent kinase 1), the upstream activator of PKB. These results identify the muscle-specific isoform FLNc as a new physiological substrate for PKB.
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PMID:Identification of filamin C as a new physiological substrate of PKBalpha using KESTREL. 1546 88

Malignant gliomas are the most common form of primary brain tumors in adults. Despite advances in diagnosis and standard therapies such as surgery, radiation, and chemotherapy, the prognosis remains poor. Recent scientific advances have enhanced our understanding of the biology of gliomas and the role of tyrosine kinase receptors and signal transduction pathways in tumor initiation and maintenance, such as the epidermal growth factor receptors, platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs such as small molecular inhibitors of these receptors and signaling pathways are showing some activity in initial studies. As we learn more about these drugs and how to optimize their use as single agents and in combination with radiation, chemotherapy, and other targeted molecular agents, they will likely play an increasing role in the management of this devastating disease. This review summarizes the current results with targeted molecular agents in malignant gliomas and strategies under evaluation to increase their effectiveness.
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PMID:Targeted molecular therapy of malignant gliomas. 1646 5

A substrate for PKBalpha (protein kinase Balpha) was detected in liver extracts, and was purified and identified as CRHSP24 (calcium-regulated heat-stable protein of apparent molecular mass 24 kDa). PKBalpha, as well as SGK1 (serum- and glucocorticoid-induced protein kinase 1) and RSK (p90 ribosomal S6 kinase), phosphorylated CRHSP24 stoichiometrically at Ser52 in vitro and its brain-specific isoform PIPPin at the equivalent residue (Ser58). CRHSP24 became phosphorylated at Ser52 when HEK-293 (human embryonic kidney) cells were stimulated with IGF-1 (insulin-like growth factor-1) and this was prevented by inhibitors of PI3K (phosphoinositide 3-kinase), but not by rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] or PD 184352, an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade and hence the activation of RSK. IGF-1 induced a similar phosphorylation of CRHSP24 in ES (embryonic stem) cells from wild-type mice or mice that express the PDK1 (3-phosphoinositide-dependent kinase 1) mutant (PDK1[L155E]) that activates PKBalpha normally, but cannot activate SGK. CRHSP24 also became phosphorylated at Ser52 in response to EGF (epidermal growth factor) and this was prevented by blocking activation of both the classical MAPK cascade and the activation of PKBalpha, but not if just one of these pathways was inhibited. DYRK2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated CRHSP24 at Ser30, Ser32 and Ser41 in vitro, and Ser41 was identified as a site phosphorylated in cells. These and other results demonstrate that CRHSP24 is phosphorylated at Ser52 by PKBalpha in response to IGF-1, at Ser52 by PKBalpha and RSK in response to EGF, and at Ser41 in the absence of IGF-1/EGF by a DYRK isoform or another proline-directed protein kinase(s).
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PMID:Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. 1591 Feb 84

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
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PMID:Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity. 1611

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.
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PMID:Targeted therapy in renal cell carcinoma. 1618 67

Malignant gliomas are the most common form of primary brain tumors in adults. Despite advances in diagnosis and standard therapies such as surgery, radiation, and chemotherapy, the prognosis remains poor. Recent scientific advances have enhanced our understanding of the biology of gliomas and the role of tyrosine kinase receptors and signal transduction pathways in tumor initiation and maintenance, such as the epidermal growth factor receptors, platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and the Ras/Raf/mitogen-activated protein (MAP)-kinase and phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways. Novel targeted drugs such as small molecular inhibitors of these receptors and signaling pathways are showing some activity in initial studies. As we learn more about these drugs and how to optimize their use as single agents and in combination with radiation, chemotherapy, and other targeted molecular agents, they will likely play an increasing role in the management of this devastating disease. This review summarizes the current results with targeted molecular agents in malignant gliomas and strategies under evaluation to increase their effectiveness.
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PMID:Targeted molecular therapy of malignant gliomas. 1586 84

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3'-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non-small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3'-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non-small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib.
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PMID:Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. 1712 14


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