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EGFR activates AKT. 1000 / 1107
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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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"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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"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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"The binding levels of 10 mg/ml Bi-Ab with HT-29 / SKOV-3 cells were 46.5 / 40.6%, that of mAb-04 and cetuximab were 33.5 / 27.1% and 61.4 / 64.0%, respectively.Bi-Ab inhibits phosphorylation of EGFR and VEGFR2 and down-regulates PI3K and AKT and MAPK signalingTo analyze the synergistic blocking of both EGFR and VEGFR2 through the antibodies (Combi or Bi-Ab) in PI3K and AKT and MAPK signaling pathway, we examined the phosphorylation of EGFR, VEGFR2, AKT and Erk1/2 in HT-29 and SKOV-3 cells treated with the antibodies."
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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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"A recent study found that arsenic exposure can lead to IL-8 overexpression via the phosphorylation of human epidermal growth factor receptor 2 (HER2), promoting migration and EMT while activating ERK (extracellular signal-regulated kinase), AKT, and STAT3 (signal transducer and activator of transcription 3) signaling pathways to increase cancer stem cell markers such as CD44 in bladder epithelial cells."
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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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"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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"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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"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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"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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"To test this, we treated HCC827 cells with a series of inhibitors targeting EGFR or EGFR-driven downstream pathways (RAF-MEK-ERK, PI3K/Akt and JAK/STAT pathway), only small molecules targeting EGFR and BRAF showed inhibitory effect on TET2 protein level (Supplementary Fig. 5a, b)."
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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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"A recent study suggested that exosomes can transfer wild-type EGFR, which, upon internalization by EGFR-mutated cancer cells, activates downstream PI3K/AKT and MAPK signaling pathways, thereby conferring osimertinib resistance to EGFR-mutated sensitive cancer cells both in vitro and in vivo ."
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"Serum withdrawal triggers EGFR-dependent activation of the PI3-kinase/Akt pathway in neuroblastoma cells, resulting in the phosphorylation of the Sp1 transcription factor and the induction of P2X7R expression, which promotes cell proliferation in the absence of trophic support [44]."
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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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"The main reason for the slowdown of glycolysis is the ability of XN to inhibit EGFR (Epidermal Growth Factor Receptor), which activates the AKT kinase complex, whose AKT1 isoform participates in cell proliferation through protein synthesis, while the AKT2 isoform is responsible for metabolism, including glycolysis, thus contributing to cell apoptosis due to the lack of lactate and high pH [ xref ]."
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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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"In studies conducted during the early phase of T. gondii infection, we showed that invasion by T. gondii causes epidermal growth factor receptor (EGFR) signalling in various cell types from humans and rodents (epithelial cells, endothelial cells, and microglia), and two signalling pathways downstream of EGFR signalling enable the parasite to activate Akt and STAT3, negative regulators of autophagy that protect the parasite from initial targeting by autophagy (Muniz‐Feliciano et al., 2013; Portillo et al., 2017)."
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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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"Knockout of ANO1 will reduce the phosphorylation of EGFR in breast cancer cells, further inhibit the activation of AKT, SRC, and ERK, and reduce the autocrine of EGFR ligands, EGF and TGF-β, suggesting that ANO1 may increase EGFR ligands The autocrine activates EGFR signal transduction (22)."
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"It has been suggested that activation of PI3K–AKT by EGFR and other RTKs may be necessary for biochemical memory and sensing of time-varying signals ( xref ), mediated by AKT-induced receptor recycling ( xref ) as well as PI3K-dependent activation of NADPH oxidase ( xref , xref )."
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"Above‐mentioned data indicate over‐activation of the MAPK and PI3K/AKT cascades and suggest that downregulation of these pathways could be an efficient form of therapy in MM.Due to our earlier observation
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that epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) inhibitors reduce the activation of the MAPK and PI3K/AKT signalling pathways, and thus significantly decrease the viability and invasion of CM, we decided to test whether these drugs would also be effective in MM."
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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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"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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"For example, Shikonin, a natural naphthoquinone isolated from the roots of Lithospermum erythrorhizon, can induce apoptosis and necrotic of GBM cells (35) by inhibiting EGFR phosphorylation and decreasing phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCγ1."
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"Mechanistically, HER2‐103aa induced the formation of epidermal growth factor receptor (EGFR)/EGFR homodimer and/or EGFR/HER3 heterodimer to maintain AKT phosphorylation, activate the downstream PI3K‐AKT pathway and promote triple‐negative breast cancer cell proliferation and progression."
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"It is reported that epidermal growth factor receptor (EGFR) activates the PI3K/AKT pathway, which may lead to the activation of IKK, IKBa phosphorylation on serine 32/36, NF-kb translocation and HER-2 signaling through protein kinase (Ck-2), which results in the NF-kb transactivational activity (Figure 4)."
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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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"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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"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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"Future investigation of these signaling axes may inform on whether or not the ERBBs regulate angiogenesis and cellular transformation in KSHV infected cells.Our working model of ERBB signaling supported by these studies suggests that ERBB1 and ERBB2 coupled signaling activates AKT and likely other downstream intermediates to promote KSHV latency."
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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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"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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"The potential mechanism of these ARGs were diverse; for example, CDH2, also known as N‐cadherin, could confer anoikis resistance in esophageal carcinoma with high intracellular PKCK2 activity. xref PARP1 enhances LUAD metastasis through promoting anoikis resistance. xref LAMB3, a regulator of the integrin‐FAK‐Src pathway, promotes cancer progression by anoikis resistance. xref ANGPTL4 has also been revealed to enhance anoikis resistance and tumor metastasis via the upregulation of MMP‐1 expression in head and neck squamous cell carcinoma. xref In hepatocellular carcinoma, anoikis resistance of hepatoma cells has been determined to require PAK1 activity, xref and CAV1 could also confer resistance of hepatoma cells to anoikis by activating the IGF‐1 pathway. xref Moreover, ITGB4 promotes metastasis of hepatocellular carcinoma by conferring anchorage independence through EGFR‐dependent FAK‐AKT activation. xref HMGA1 promotes anoikis resistance through a PI3K/Akt‐dependent mechanism in pancreatic adenocarcinoma. xref PLK1 protects esophageal carcinoma cells from anoikis through regulating β‐catenin protein levels. xref Additionally, TIMP1, integrating with CD63 and β1‐integrins as a complex, confers anoikis resistance by activating PI3K signaling pathway in melanoma. 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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"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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"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 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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"Additionally, exosomal EGFR can activate the AKT and MAPK signaling pathway to human umbilical vein endothelial cells (HUVECs) by conveying cancer cell-derived EGFR signals, which is accomplished via the presentation of intact EGFR kinase activity and phosphatidylserine (PS) [57,59]."
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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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"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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"To determine whether cetuximab inhibits the EGFR-mediated downstream signaling of AKT and ERK in the bladder cancer cells, these cells were treated with cetuximab at a final concentration of 100 μg/ml for 36 h. Subsequent western blot analysis revealed that the phosphorylated forms of AKT and ERK1/2 were downregulated by cetuximab in HT1376 and 5637 cells (Fig. 2A)."
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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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"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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"EGFR-mutant NSCLC cells with increased EGFR tyrosine kinase activity excessively activate multiple EGFR-mediated downstream signaling pathways, such as MAPK, PI3K/AKT, and STAT3 pathways, consequently promoting the overexpression of CSC biomarkers and enhancing the stem-like properties of the cells [32,33,34,52]."
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"Focusing on signaling pathways, our analyses found that proteins impacted by epiHSP70s in MDA-MB-468 cancer cells would result in activation of constitutive EGFR signaling, activated AKT and PTEN stabilization, oncogenic MAPK signaling, non-canonical NFκB signaling, constitutive NOTCH1 signaling, RhoGTPase activation of formins, β-catenin defective regulation, toll-like receptor cascades and aberrant death receptor signaling."
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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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"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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"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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"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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"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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"The biological effects of EGF are exerted by binding to EGF receptor (EGFR), which activates Ras/mitogen-activated protein kinase (Ras/MAPK), phosphatidylinositol 3-kinase/AKT (PI3K/AKT) and phospholipase C-kiγ/protein after the autophosphorylation of receptor tyrosine kinase (RTK) ."
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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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"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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"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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"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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"The biological effects of EGF are exerted by binding to EGF receptor (EGFR), which activates Ras/mitogen-activated protein kinase (Ras/MAPK), phosphatidylinositol 3-kinase/AKT (PI3K/AKT) and phospholipase C-kiγ/protein after the autophosphorylation of receptor tyrosine kinase (RTK) ."
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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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"Activation of the EGFR family by epidermal growth factor (EGF) stimulates the downstream phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways, which promotes increased AR transactivation, transcriptional activity, and CRPC development (16, 17, 18)."
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"EGFR alterations with subsequent protein overexpression activate a plethora of signaling pathways, including PI3K/Akt and extracellular signal-regulated kinase (ERK1/2), which promote tumor proliferation, resistance to apoptosis, chemoradioresistance, and GBM tumor recurrence [10]."
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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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"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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"Upon binding to its ligand, EGFR forms an active homodimer or heterodimerizes with other ErbB family members such as HER2, leading to activation of mitogen-activated protein kinase (MAPK), AKT, c-Jun N-terminal kinase (JNK), and phosphoinositide phospholipase C/protein kinase C (PLC/PKC) signaling pathways that are involved in cell growth, proliferation, migration, and differentiation."
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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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"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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"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 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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"EGFR mediates the activation of Janus kinase/signal transducer and activator of transcription 3 (STAT3) (Ueno et al, 1997); AKT, involved in cell survival; and ERK1/2, which regulates cell stress and proliferation (Meloche & Pouysségur, 2007; Lill & Sever, 2012; Goffin & Zbuk, 2013)."
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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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"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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"EGFR pathway substrate 8 (EPS8) is a vital protein which mediates EGFR‐induced activation of Akt and ERK. xref It significantly promotes the proliferation by inducing expression of focal adhesion kinase (FAK). xref , xref It also found to induce resistance in cancer cell lines against chemotherapeutic drugs. xref "
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"These pathways can become activated independent from EGFR signaling through mutations in downstream pathway components in cetuximab-resistant CRC, but it is possible that RAC1 overexpression could also contribute to pathway activation, as RAC1 interacts with many EGFR signaling effectors.RAC1 has been shown to activate the Ras/MAPK, PI3K/AKT, and STAT signaling pathways, and these pathways in turn also activate RAC1 (Figure 3B) [102,103]."
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"Mutant forms of EGFR associated with glioma exhibit constitutive kinase activity, long-term stimulation of RAS signaling to promote cell cycle progression, and activation of the PI3K/AKT pathway to promote cell proliferation and migration (Rong et al., 2009; Ivliev et al., 2010; Mazzoleni et al., 2010)."
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"We hypothesize that this is due, in part, to the markedly differing thresholds of EGFR stimulation required to fully activate the PI3K/AKT versus RAF/MEK/ERK cascades; small amounts of EGFR stimulation are needed to fully activate RAF/MEK/ERK signaling, whereas 5‐ to 10‐fold higher levels of EGFR stimulation are required to activate the PI3K/AKT pathway."
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"A role for EGFR in the suppression of apoptosis by PAR2 activation has also been proposed with studies showing that activation of PAR2 in cultures of lung cancer cells led to suppression of apoptosis either by induction of EGFR expression and decreasing the ratio of Bax : Bcl-x (Huang et al., 2013) or through EGFR transactivation mediated induction of Akt (Michel et al., 2014)."
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"A disintegrin and Metalloprotease 17(ADAM17), the target of miR-145, is also a major upstream component of several EGFR precursor ligands (Zheng et al., 2007; Lu et al., 2013), which activate MEK/ERK and PI3K/Akt when EGFR binds to the ligands, leading to aggressive and other malignant phenotypes (Tsatas et al., 2002)."
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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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"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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"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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"EGFR phosphorylation initiates multiple downstream signaling pathways, including the mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinases/protein kinase B (also known as AKT), and the Janus kinase (JAK)/STAT pathway (1), and accordingly affects several fundamental cellular processes, such as cell proliferation, cell metabolism, and survival (13)."
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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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"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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"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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"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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"These findings suggest that DR1 activation increases endogenous H S production, which inhibits HG-induced VSMCs proliferation by down-regulating IGF-1/IGF-1R and HB-EGF/EGFR, as well as their downstream PI3K/Akt, JAK2/STAT3 and ERK1/2 pathways.The above experimental results confirmed that DR1 activation inhibits VSMCs proliferation by increasing endogenous H S production in T1MD mice and HG-induced VSMCs."
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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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"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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"Serum withdrawal triggers EGFR-dependent activation of the PI3K/Akt pathway in neuroblastoma cells, inducing the upregulation of P2rx7 gene expression, which in turn promotes the survival/proliferation of cancer cells in the absence of trophic support (Gomez-Villafuertes et al., 2015)."
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"Three eicosanoid products have a pivotal significance in downstream proangiogenic activities such as VEGF production, facilitation of blood vessel sprouting, migration, and tube development [233], improved endothelial cell survival via activating Akt production and increasing Bcl-2 level [234], stimulation of MMPs, initiation of EGFR-driven angiogenesis, and inhibition of interleukin-12 generation [235]."
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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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"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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"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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"Knockdown of MICALL2 inhibited AKT and mTOR phosphorylation; it is suggested that knockdown of MICALL2 inhibits EGFR expression and reduces the endogenous activation of the AKT–mTOR signaling pathway, thereby downregulating MMP9 mRNA and protein expression.This study also explored the mechanism through which MICALL2 regulates the stabilization of EGFR."
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"Using an external scoring function (TIGER software) for target prediction proved useful in this study, complementing the twin-CLM approach.To confirm the biological activities of the most potent compounds 18 (K = 52 nM) and 22 (K = 13 nM) in cells, we tested compound effects on epidermal growth factor receptor (EGFR)-induced activation of AKT/protein kinase B (PKB), a well-established effector downstream of EGFR-PI3K signaling in cancer ."
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"For instance, circRAB11A modulates the proliferation and apoptosis of chicken GCs by sponging miR-24-5p, which in turn regulates RAB11A, member RAS oncogene family (RAB11A) and Epidermal growth factor receptor (EGFR), activating the PI3K/AKT and Extracellular signal-regulated kinase (ERK) signaling pathways (Wei, et al., 2024a)."
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"myocyte death via apoptosis (FO3A and BAD) and ER stress Energy production (ATP) dysregulationABL and ARG pathway dysregulation crucial to myocyte cellular homeostasis c-KIT inhibition leading to impaired myocyte vascular responseImpaired ERBB2 mediated myocyte cellular homeostasis Possible EGFR off-target inhibition EGFR mediated Akt and MAPK dysregulation crucial for myocyte cycle Possible increased platelet activity mediated by ADP and TXA2 Decreased atherosclerotic plaque stability from impaired myocardial repair mechanismABL : An oncogene; AMP : Adenosine monophosphate; ARG : ABL related gene; ATP : Adenosine triphosphate; BAD : BCL-2-associated death promoter; BCL-2 : B-cell-related lymphoma-2 protein; c-KIT : Mast/stem cell growth factor or proto-oncogene; CSF : Colony stimulating factor; ER : Endoplasmic reticulum; ERK : Extracellular signal regulated kinases; FLT3 : FMS related tyrosine kinase; FO3A : forkhead box O3A; HIF : Hypoxia inducible factor; JNK : C-Jun N-terminal kinases; PDGFR : Platelet derived growth factor receptor; RAF : Proto-oncogene; RAS : GTPase derived from rat sarcoma; RET : A protooncogene; SRC : Proto-oncogene tyrosine kinase derived from sarcoma; TKI : Tyrosine kinase inhibitor.data suggest that patients with pre-existing cardiac disease need to be screened diligently to prevent significant cardiac toxicity [10-12]."
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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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"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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"Importantly, the EGFR expression and the EGFR/AKT pathway were restored in the CD109-KO cells (Figure 6C lane 2 vs. lane 5), further demonstrating that localization of EGFR at the membrane rescues the EGFR/AKT pathway to levels comparable to that of control A431 cells (Figure 6D)."
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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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"The prolonged, strong activation of Akt modulates ERK1/2 activity, possibly through indirect phosphorylation of Raf, or attenuation of MEK activity, resulting in the upregulation of EGFR gene expression. (B) Binding of EGF to EGFR co-activates ERK1/2 and Akt, however, prolonged activation of Akt does not affect the strong induction of ERK1/2."
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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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"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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"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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"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."