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"Since PGE 2 transactivates EGFR via an intracellular signaling pathway [XREF_BIBR] and PGE 2 can also directly activate the PI3K-AKT pathway in an EGFR independent manner (XREF_FIG), we hypothesize that activation of PGE 2 signaling could affect clinical response to the anti-EGFR therapy."
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"Increased expression of Lewis y antigen activates EGFR and HER2 and neu receptor tyrosine kinases, which further activate the PI3K and Akt and Raf/MEK/MAPK signal transduction pathways downstream of EGFR, resulting in accelerated transcription of HER2 and neu genes in the nucleus and stimulation of DNA synthesis and ultimately promotes the cells to skip G1 phase into S phase, promoting cell proliferation and other kinds of malignant behavior [XREF_BIBR]."
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"These results suggest that BPDE induced transformation requires EGFR mediated Akt and ERK activation, and that MUC1 plays a lung cancer promoting role during lung cancer development, at least partly through mediating carcinogen induced activation of the EGFR mediated cell survival pathways that neutralize carcinogen 's cytotoxicity to facilitate cell transformation (XREF_FIG)."
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"Thus, APC activates Tie2, via a mechanism requiring, in sequential order, the receptors, endothelial protein C receptor, protease activated receptor-1, and EGF receptor, which selectively enhances the PI3K and Akt signaling to enhance junctional complexes and reduce keratinocyte permeability."
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"This system results in focal gliomas, the subtype and grade of which varies with the injected retrovirally transduced gene (i.e. PDGFB, EGFRvIII, activated p21-RAS, activated AKT), the lineage of the cell expressing the tva receptor (GFAP, NES) and underlying genetic cell cycle alterations in the mice (null for Cdkn2a, Trp53 etc.)."
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"Next, we sought to explore whether p53-R175H-induced PI3K and AKT signaling is mediated by EGFR activation, we pretreated KLE cells with specific EGFR tyrosine kinase inhibitor PD153035 (20 muM) for 2 h. Western blot analysis indicated that PD153035 significantly inhibited p53-R175H-induced EGFR and AKT activation."
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"Here, we show BRCA1-IRIS overexpression is involved in TNBCs intrinsic and acquired paclitaxel resistance, through, in part, increasing expression and activation of autocrine signaling loops involving epidermal growth factor receptor 1 (EGFR) and epidermal growth factor receptor 3 (ErbB3) that activate AKT leading to FOXO3a degradation and survivin overexpression."
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"Asbestos fibers activate epidermal growth factor receptor (EGFR) and other receptors leading to activation of the mitogen activated protein kinase (MAPK) pathway including p38, c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK1/2) as well as AKT that can modulate apoptosis [XREF_BIBR, XREF_BIBR]."
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"Similar to GLP-1-induced beta-cell proliferation, antiapoptotic effects of GLP-1 in beta cells are mediated by promotion of FoxO1 nuclear exclusion and consequent up-regulation of PDX-1 and Foxa2 expression via EGFR- and PI-3K-dependent activation of PKB and cAMP and PKA dependent activation of CREB, leading to up-regulation of Irs2 protein expression and activation of PKB (XREF_FIG)."
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"It has also been noticed that the EGFR amplification is often accompanied by an upregulated expression of the deletion mutant EGFR variant III form, also designated as EGFRvIII or DeltaEGFR, as well as the PTEN loss induced Akt activation, and associated with a poor overall survival of GBM patients."
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"XREF_BIBR - XREF_BIBR Oxidative stress due to cigarette smoke induces non canonical EGFR autophosphorylation at Src dependent phos phorylation sites leading to recruitment of Src to EGFR, which triggers the Ras/Raf/MEK/ERK and PI3K and AKT signalling cascades and contributes to tyrosine kinase inhibitor resistance in tyrosine kinase inhibitor sensitive lung cancer cells."
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"Nonetheless, in transient assays WT ERRFI1 displayed characteristics of a tumor suppressor, inhibiting EGF-induced neuroblastoma cell growth and migration, EGFR phosphorylation, as well as EGF-induced PI3K/AKT and MAPK/ERK pathway activation in isogenic SH-SY5Y, SK-N-AS, and NLF neuroblastoma cells (Figure 7F–H, Supplementary Figure 3I, J)."
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"For example, constitutive activation of EGFR or K-RAS that is due to mutation subsequently upregulates the Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/v-akt murine thymomaviral oncogene (AKT) signaling pathways, which triggers a cascade of downstream effectors promoting tumor growth, angiogenesis, and metastasis [50,51]."
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"As HER2 and EGFR can activate Akt (although HER2 would be its dominant activator in breast cancer) and Akt in turn can promote cell survival, the observed inhibition of cell growth following JAM-A knockdown in drug-resistant models may reflect downregulation of HER2, EGFR, and pAkt."
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"The GLP-1 receptor activation in beta-cells leads to IRS-2 and PKB activation mediated by CREB and transactivation of EGFR [XREF_BIBR] Constant entry of glucose into the beta-cell leads to a state of reversible insensitivity to glucose stimulation concomitant with an exhaustion of beta-cell stores."
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"Since betaAR mediated EGFR transactivation has been shown to promote survival [XREF_BIBR], and ERK1/2 and Akt are known regulators of apoptosis we next investigated the ability of betaAR mediated transactivation to modulate early apoptotic signaling events by assessing caspase activation."
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"For example, Huang et al. [XREF_BIBR] conducted a large-scale analysis of phosphotyrosine mediated signaling pathways using U87MG GBM cells stably expressing EGFRvIII and subsequently found that EGFRvIII preferentially activates PI3-K and Akt over the Ras and MAPK and STAT3 pathways."
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"Although we did not find known mutations previously detected in lung cancer, our data are consistent with previous preclinical studies in lung cancer cells that harbor EGFR mutations ( xref – xref , xref ), in which the drug sensitivity to gefitinib is closely correlated with EGFR-dependent AKT activation."
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"Since cell proliferation and migration are the two major factors that contribute to the movement of cells away from the edge of the explants and stimulation of EGFR by exogenous EGFR ligand, epiregulin also promotes both proliferation and migration in RPTC though a PI3K and Akt dependent mechanism, these results suggest that EGFR dependent activation of the PI3K and AKT pathway may act downstream of Src to mediate these regenerative responses."
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"Indeed, we determined that EGFR was substantially activated in response to glutamine starvation, as measured by the extent of EGFR phosphorylation and the activation of downstream effector pathways, such as Erk and Akt, which were suppressed by EGFR inhibition (XREF_FIG and XREF_SUPPLEMENTARY - XREF_SUPPLEMENTARY)."
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"Both PD153035, an inhibitor of EGFR, and GW2974, a dual specific inhibitor of EGFR and erbB2, effectively reduced activation of Akt and a downstream effector, Fox01/03 (forkhead family of transcription factor), following treatment with TPA as well as TPA stimulated EGFR and erbB2 tyrosine phosphorylation in a dose dependent manner in mouse skin [XREF_BIBR]."
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"Importantly, the ability of EGF to activate EGFR, and therefore Akt and Erk, increasing neuroprotection from excitotoxicity following glutamate administration, is restored by expression of exogenous EGFR in PS1-null cortical neurons indicating that PS1 regulates EGFR expression in EGF neuroprotection [178]."
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"Altogether, these results indicate that betaAR mediated EGFR transactivation directs differential subcellular ERK1/2 and Akt activation, with a strong influence on nuclear signaling events, including the negative regulation of pro apoptotic TRAIL expression, to ultimately promote cardiomyocyte survival."
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"The region we describe here has also recently been identified by another group to contain a T-cell transcription factor (TCF) -4 and Sp1 binding site that was found to be important for transcription and activated by human epidermal growth factor receptor (HER) -2 activation of the AKT and beta-catenin pathway [XREF_BIBR], which points to the importance of this region in driving the transcription of Jab1 and possibly linking its expression to potent oncogenic signaling pathways."
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"In addition, tunicamycin treatment of cells reduces the cycling of EGFR to the cell surface, increasing retention of EGFR in the endoplasmic reticulum (ER): this is accompanied by a decrease in EGFR-dependent AKT activation, and radiosensitization of tumor cells in glioma and pancreatic cancer models [ xref ]."
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"betaAR mediated EGFR transactivation has also been shown to increase phosphorylated ERK1/2 (P-ERK1/2) and Akt (P-Akt) in both the heart and isolated cardiomyocytes, and has been shown to exert differential subcellular targeting of P-ERK1/2 in non cardiac cells [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"In conclusion, the inhibition of EGFR suppressed downstream pathways (the JAK1/2/-STAT3 and AKT and MDM2 signaling axis), causing the up-regulation of P53 expression and the down-regulation of cell cycle related gene expression, thereby arresting cell cycle at the G0/G1 phase and promoting cell apoptosis in EsC cells."
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"XREF_BIBR Highly expressed EGFR activates the downstream PI3K and Akt signaling pathway, inhibits cellular apoptosis induced by multiple stimuli, promotes cell survival and proliferation, participates in angiogenesis, transmits integrin mediated invasion signals, and plays an important role in the formation, proliferation, and metastasis of tumors."
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"Using a model of the effect of Akt activation on cell response, Purvis et al. showed that preferential Akt activation is conducive for the cell to rely on ErbB1 mediated Akt activation for generation of pro survival signals while requiring the initiation of death inducing signals from other pathways."
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"A number of growth factors, such as IGF-1, via AKT activation, but also receptor tyrosine kinases, such as EGFR, via Ras, as well as Wnt, ultimately lead to phosphorylation and consequently inactivation of the TSC complex, thus allowing mTOR to signal in principle [[127], [128], [129]]."
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"When determining Akt phosphorylation on Thr308 as an indicator of PI 3-kinase activation, we observed that coactivation of EGFR and PDGFRbeta induced a similar level of Akt activation in wt fibroblasts as that observed after activation of PDGFRbeta in H-RasG12V-transformed fibroblasts."
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"XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR Several prosurvival pathways have been reported to be variably activated by EGFR and other signals in SCCHN, including the Mitogen Activated Protein Kinases (MAPKs), AKT, Nuclear Factor-kappa B (NF-kappaB), and Signal Transducer and Transcription (STAT) -3 pathways."
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"XREF_FIG, knockdown of endogenous EGFR by shRNA targeting the 5 '-UTR of endogenous EGFR failed to activate mTOR or Akt, and most importantly failed to upregulate LC3B-II, supporting that EGFR can suppress the mTORC2 and Akt pathway and autophagy independent of EGFR 's kinase activity."
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"Since EGFR and HER3 can activate PI3K and Akt through different recruitment paths [XREF_BIBR], when they compete for the limited PI3K and Akt signaling capacity, the amount of Akt phosphorylation reflects the balance between the relative contributions of the EGFR (weak Akt activator) and HER3 (strong activator) pathways."
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"Especially for the case of EGFR‐dependent AKT activation there has been a lot of controversy: while several studies found amelioration of kidney injury through AKT activation (Sinha et al. xref ; Chen et al. xref ; Jang et al. xref ; Kalmar‐Nagy et al. xref ; Ghosh et al. xref ; Mohamed et al. xref ), other studies showed deleterious effects (Bollee et al. xref ; Tang et al. xref ; Yamamoto et al. xref )."
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"In particular, ADAM17 released amphiregulin promotes proliferation and motility of head and neck squamous cell carcinoma, and amphiregulin and/or HB-EGF activated by ADAM17 stimulated EGFR and consequent activation of MAPK/ERK1/2 and prosurvival AKT signaling in squamous cell carcinoma or lung cancer."
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"Since EGFR kinase inhibition by erlotinib diminishes activation of both ERK and AKT pathways in drug sensitive cells but not in drug resistant cells (XREF_FIG and XREF_FIG A), we next asked whether inhibition of both pathways is required for the increased expression and dephosphorylation of BIM."
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"In this study, we found that early in the TGEV infection process, APN and EGFR synergistically stimulate PI3K/AKT and MEK/ERK1/2 signaling pathways, and promoted TGEV entry.Many pathogens enter the host cell by endocytosis which results in cell surface receptor, ligand, and membrane component internalization (Mosesson et al., 2008)."
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"Together, these results suggested that MET, EGFR, HER2, and HER3 activate AKT and ERK signalling pathways and promote cell proliferation and survival in lung cancer cells with MET amplification, whereas MET, HER2, and RET activate the STAT3 signalling pathway and promote cell migration."
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"One study reported the differences in carcinogenic molecular genetic pathways between EGFR mutation tumors and tumors with wild-type EGFR . xref The results showed that mutant EGFR selectively activated Akt and signal transducer and activator of transcription (STAT) signaling is related to cell survival; however, mutant EGFR could not act on extracellular signal-regulated kinase signaling, the function of which is to induce proliferation."
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"Because BPDE stimulated EGFR mediated Akt and ERK activation that was associated with MUC1 overexpression (XREF_FIG) and MUC1 modulates EGFR activation in breast epithelial cells XREF_BIBR, XREF_BIBR, we examined if MUC1 is involved in BPDE induced activation of EGFR mediated Akt and ERK pathways."
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"In NSCLC cells, HER3 couples with EGFR to activate the PI3K and AKT pathway in gefitinib sensitive NSCLC cell lines, but not gefitinib resistant lines, suggesting that NRG1 bound HER3 may predominantly dimerize with RTKs other than EGFR to promote acquired resistance to TKIs [XREF_BIBR]."
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"The abnormal overexpression or activation of AKT has been observed in cancers including lung, ovarian and pancreatic cancers (33), and AKT could be activated by epidermal growth factor receptor (EGFR) (34), implying that targeting EGFR or AKT could offer important approaches for cancer prevention and therapy."
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"Seven of nine SRC family kinase genes are included among 18 genes that encode proteins that modify the EGFR dependent cell growth and survival of lung cancer cells that harbor an activated mutant EGFR, [XREF_BIBR], suggesting EGFR independent activation of the MEK and ERK and PI3K and AKT signaling pathways [XREF_BIBR]."
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"In this study, overexpression of PFKP was detected in human glioblastoma (GBM) and resulted from AKT activation that, in turn, was induced by phosphatase and tensin homologue (PTEN) loss and epidermal growth factor receptor (EGFR)-dependent phosphoinositide 3-kinase (PI3K) activation."
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"The abnormal overexpression or activation of AKT has been observed in cancers including lung, ovarian and pancreatic cancers ( xref ), and AKT could be activated by epidermal growth factor receptor (EGFR) ( xref ), implying that targeting EGFR or AKT could offer important approaches for cancer prevention and therapy."
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"Some of the cell signaling events associated with these responses include TRPV1 transactivation eliciting epidermal growth factor receptor (EGFR) signaling cascades, which in turn lead to global MAPK and Akt/PI-3K pathway stimulation in SV40-immortalized human corneal epithelial cells (Pan et al. 2011)."
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"While the molecular mechanism of how UVRAG regulates mitochondrial function is not entirely clear, we can postulate that activated Akt signaling by EGFR accumulation that we observed in the M-UVRAG -/- mice can potentially inhibit transcription of mitochondrial biogenesis and function through decreased Pgc1alpha expression."
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"Overexpression of EGFR induces downstream PI3K/Akt and JNK/STAT intracellular signaling pathways (7, 8) that result in provoking enhancements in a plethora of biological functions, such as promotion of cell proliferation, protection against apoptosis, acceleration of invasion, and angiogenesis (9)."
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"6 ROR1 sustains EGFR mediated PI3K-AKT prosurvival signaling and inhibits ASK1-p38 MAPK proapoptotic signaling in both kinase dependent and kinase independent manners, 6, 9 while it also maintains caveolae structure and caveolae dependent endocytosis by functioning as a scaffold protein for caveolin-1, cavin-1, and cavin-3 in a kinase independent fashion, and sustaining prosurvival signaling of other receptor tyrosine kinases (RTKs) including MET and IGF1R."
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"Furthermore, the Chlamydomonas derived peptide, H-P-6 (Pro-Gln-Pro-Lys-Val-Leu-Asp-Ser), has been shown to suppress H. pylori induced hyperproliferation and migration of AGS cells by a mechanism that involves epidermal growth factor receptor (EGFR) activation of the PI3K-Akt pathway and GSK3beta inactivation [XREF_BIBR]."
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"Using the experimental data collected for Erk and Akt activation mediated by EGFR and HER2, we have shown that a module based analysis of the dynamical properties of biological networks is feasible, and that it can be an informative approach to understand the inherent dependencies in the experimental data."
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"Epidermal growth factor receptor (EGFR) mutations enable constitutive active downstream signaling of PI3K and AKT, KRAS and ERK and JAK and STAT pathways, and promote tumor progression by inducing uncontrolled proliferation, evasion of apoptosis and migration of non small cell lung cancer (NSCLC)."
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"In cancer, HCK activation interacts with receptor tyrosine kinases (RTK), such as platelet-derived growth factor receptor (PGDFR), epidermal growth factor receptor (EGFR), and fibroblast growth factor receptor (FGFR), activating ERK, AKT, and STAT3 signaling pathways, further stimulating cell proliferation [14]."
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"Taken together, our data suggest that PLC-gamma1 is stimulated in part through EGFR for efficient replication in A549 cells, whereas Akt can be stimulated by virus infection independent of EGFR, and is not essential for virus productive infection, indicating that Akt modulates BoHV-1 replication in a cell type dependent manner."
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"Thus, two EGFR TKI resistant cell lines (SUM159 and SUM229) and one EGFR TKI sensitive cell line (SUM149) were treated with lovastatin and gefitinib alone or in combination and immunoblotting was performed to determine the phosphorylation of two key mediators of EGFR induced survival and proliferative signaling, Akt and MAPK."
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"Since EGFR, IGF-1R and CRAF have been known to be the key components of RTK-RAS-RAF-MEK-ERK (MAPK) and/or PI3K and AKT signaling pathways, we further determined if single or combined inhibition of EGFR, IGF-1R and CRAF could suppress the activation of MAPK and PI3K and AKT signaling in VemR melanoma cells."
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"Interestingly, first-line sensitivity to EGFR TKIs in NSCLC has been associated with pre-existent Akt activation that is suppressed by EGFR inhibition, while treatment with EGFR TKIs failed to block Akt signaling in tumor cells intrinsically resistant to these drugs XREF_BIBR - XREF_BIBR."
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"The previous study reported that the EGFR increase, EGFR-mediated PI3K/Akt activation, and increased NF-κB signal activation were found to develop docetaxel resistance in CRPC (11, 12, 42), whereas this present study found reduced EGFR, PI3K, and NF-κB signal by silencing USP8 in with or without docetaxel treatment (
Figure 4A
)."
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"54 It is also demonstrated that APC activated Tie2 via a mechanism requiring, in sequential order, endothelial protein C receptor, protease-activated receptor-1, and EGF receptor, which selectively enhances the PI3K/Akt signaling to strengthen the junctional complexes and reduce vascular permeability."
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"The elevation of SHKBP1 following TGFβ-induced EMT is sustained by EGFR-independent activation of AKT because this is reduced by PI3K inhibitors, but not by erlotinib.In clinic, SHKBP1 expression level was found increased in OS samples compared with that in their adjacent normal counterparts."
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"Since several studies have already demonstrated that CD44 could be both a co-regulator and a downstream target of EGFR signaling [XREF_BIBR, XREF_BIBR] plus EGFR induced AKT could activate NF-kappaB in HCT-8 human CRC cells [XREF_BIBR], we postulated that EGFR signaling might be more active in the stemness-high GATA6 overexpressing human CRC clones."
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"Upon growth factor ligand binding to its extracellular domain and phosphorylation of its intracellular tyrosine kinase domain, EGFR becomes activated [XREF_BIBR] and initiates signal transduction cascades (Ras and MAPK and PI3K and Akt) leading to increased DNA transcription, antiapoptosis, angiogenesis, and cellular proliferation [XREF_BIBR]."
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"However, cell-permeable pseudosubstrate peptides from PKCalpha and beta, PKCeta, PKCzeta, and kinase domain of EGF receptor modified by myristoyl radical, in addition to inhibiting PKC activity, possess the ability to activate ERK1/2 and p38 MAPK, the components of MAPK cascade, and the intracellular enzymes (AKT kinase, in particular) involved in endothelial nitric oxide synthase activation and NO production [XREF_BIBR, XREF_BIBR] (XREF_TABLE)."
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"mTOR signals, activated through the RAS/MEK/ERK and PI3K and AKT pathways induced by tyrosine kinase receptors EGFR and IGFR, regulate cell growth and proliferation, cell metabolism by mediating multiple signals : growth factors, nutrients, hormones, and energy and stress status [XREF_BIBR, XREF_BIBR]."
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"As HER2 and EGFR can activate Akt (although HER2 would be its dominant activator in breast cancer) and Akt in turn can promote cell survival, the observed inhibition of cell growth following JAM-A knockdown in drug-resistant models may reflect downregulation of HER2, EGFR, and pAkt."
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"Feedback phosphorylation of EGFR at Thr669 by ERK has been found to negatively regulate constitutive EGFR tyrosine kinase activity and HER3 driven Akt activation by suppressing heterodimerization of EGFR and HER3 in lung cancer and triple negative MDA-MB-468 breast cancer cells (Sato etal., 2013; Turke etal., 2012)."
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"Because receptors for growth factors are known to transmit signals by mechanical stress XREF_BIBR, and EGF receptor transactivation induces activation of PI3K and Akt pathway XREF_BIBR, VSMC was treated with 10% MS for 4 hrs in the presence of inhibitors for various growth factor receptors, including AG1295 (a PDGFR inhibitor), AG1478 (an EGFR inhibitor), AG1024 (an IGFR inhibitor) and PD173074 (a FGFR inhibitor)."
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"We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ induced AKT activation and the pro survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H 2 O 2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown."
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"For example, EGFR activation activates PI3K-AKT and Raf-MAPK-ERK1/2 pathways XREF_BIBR, XREF_BIBR, XREF_BIBR to generate intracellular mediators which translocate into the nucleus to regulate DNA synthesis for cell growth and proliferation as well as to modulate cell survival, migration, differentiation and death XREF_BIBR, XREF_BIBR."
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"TGEV S1 protein interacts with EGFR extracellular receptor binding domain 1 to induce EGFR internalisation and promote APN and EGFR aggregation, which synergically stimulate PI3K/Akt and MEK/ERK1/2 endocytosis signalling pathways in the early stage of TGEV infection and promote TGEV entry (Hu et al. 2018)."