IndraLab

"The epidermal growth factor receptor (EGFR), which activates STAT3, is reportedly overexpressed in human pancreatic cancer cells [ xref ]."

"Butaprost also induced the activation of AKT, ERK1/2, and STAT3, all of which were inhibited by beta-arrestin deficiency or EGFR inhibition."

"In HNSCC, activation of STAT3 by IL-6 and EGFR has been proven to be a key molecular event [ xref , xref ]."

"Our studies show that poultry dust extract controls the induction of immune and inflammatory mediator levels via a cellular pathway involving oxidative stress mediated STAT-3 activation by Tyk2 and EGFR tyrosine kinases."

"In addition, EGFR also activates STAT3 in a JAK-independent mechanism [ xref ]."

"Suppressor of cytokine signaling-1 (SOCS-1) has been implicated recently in the negative regulation of IL-6R/Janus-activated kinase (JAK)-mediated activation of STAT3, suggesting that SOCS-1 could affect alternative activation of STAT3 by EGFR, IL-6R, and associated kinases."

"As noted above, Jak kinases can phosphorylate Stat3, reinforcing Egfr mediated Stat3 activation."

"Taken together, these data suggested that CD109 may be involved in the induction of EGFR-mediated STAT3 phosphorylation.To further determine the effects of EGFR in mediating CD109/STAT3 activity, the sorted CD109( + ) CaSki cells were treated with anti-EGFR antibody (2 µl/ml, Cetuximab, Cat."

"To determine whether STAT3 is differentially activated by EGFRvIII, we analyzed expression of tyrosine phosphorylated STAT3 by immunoblotting in addition to STAT3 transcriptional activity in the EGFRvIII expressing HNSCC cells compared with vector-controls."

"Full-length EGFR binds and directly activates signal transducer and activator of transcription 1 (STAT1) and STAT3 ( xref ); these function as homo- and heterodimers ( xref ; xref )."

"Our results also suggest that while activating mutations of EGFR may enhance IL-6 production and autocrine stimulation of STAT3 activity, additional cellular factors are important in modulating this pathway and the response of cells to IL6."

"Greulich et al. reported that STAT3 was activated by various EGFR mutations, including the exon 19 in-frame deletion or the exon 21 L858R point mutation, and may contribute to the oncogenic effects of these mutations in fibroblasts and human lung cancer cells [XREF_BIBR]."

"The mechanism whereby mutant EGFR drives STAT3 activation is indirect, as it requires upregulation of the cytokine IL-6, which activated the gp130 and JAK pathway [XREF_BIBR] (XREF_FIG)."

"For example, acylglycerol kinase potentiates JAK2 and STAT3 signaling in ESCC XREF_BIBR; Epstein-Barr virus (EBV)-encoded proteins constitutively activated STAT3 in NPC XREF_BIBR, XREF_BIBR; and, EGFR mutation mediates STAT3 activation via IL-6 production in lung cancer XREF_BIBR."

"NCI-H1650 is a lung adenocarcinoma cell, in which a mutant EGFR regulates the expression of the IL-6 cytokine and leads to the activation of JAK and STAT3 pathway."

"EGFR mutations activate ERK, AKT and STAT3 directly or through IL-6-JAK2 [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

"EGFR mutations activate MAPK, PI3K-AKT, and STAT3 directly or through IL-6-JAK2 (5,10,21)."

"Although STAT3 is activated by EGFR mutations [XREF_BIBR, XREF_BIBR], other receptor and non receptor tyrosine kinases such as the interleukin-6 (IL-6)/gp130 receptor can also stimulate STAT3 activation [XREF_BIBR]."

"Previous findings have shown that EGFR mutations activate STAT3 (55)."

"EGFR mutations cause abnormal activation of the downstream JAK/STAT3 signalling pathway, leading to increased expression of phosphorylated STAT3, followed by abnormal tumor growth, angiogenesis, invasion, and metastasis."

"Fig.1"

"Fig.1"

"Modified assertion"

"The stimulatory EGFR signal is insensitive to inhibition of JAKs and appears to involve Src kinases and STAT proteins as shown by inhibition through overexpression of C-terminal Src kinase (Csk) and transdominant negative STAT3, respectively"

"To explore this further, we have blocked endogenous ErbB3 transcription, thereby engineering tumor cells with overexpressed, fully active ErbB2 but lacking ErbB3 (T. Holbro and N.E. Hynes, unpublished data). As a consequence, these cells have decreased PI-3K/PKB signaling, a reduction in D-type cyclin levels, and show an increase in the G1 phase of the cell cycle. A main effector of ErbB signaling, the PI-3K/PKB pathway, is particularly important in mediating cell survival 103 T. Holbro et al. / Experimental Cell Research 284 (2003) 99-110 since several PKB substrates directly control various apoptotic processes. The proapoptotic Bcl family member Bad, when phosphorylated by PKB [93], is retained in the cytosol where it is unable to inhibit survival proteins like Bcl-XL on the mitochondria [94]. In normal mammary cells, blocking ErbB1 activity leads to apoptosis by lowering phospho-Bad levels, [95], a characteristic that would be extremely desirable to retain in cancer cells. Another PKB target is caspase-9, whose activation is blocked by phosphorylation [96] Members of the forkhead family of transcription factors, when phosphorylated by PKB, are retained in the cytoplasm and are unable to stimulate expression of several critical genes for apoptosis, including FasL, BIM, and others (reviewed by Brunet et al. [97]). Moreover, PKB phosphorylates IKK-alpha, which in turn inactivates IkappaB, thus leading to activation of NF-kappaB. This transcription factor upregulates levels of the prosurvival Bcl-XL protein and several inhibitors of apoptosis (IAPs) (reviewed by Datta et al. [98]). In this regard, it has been reported that cell lines overexpressing ErbB2 are resistant to TNF-induced apoptosis through a PKB/NF-B pathway [99]. Another ErbB effector protein, signal transducer, and activator of transcription (Stat) has been implicated in survival of squamous cell carcinomas of the head and neck. ErbB1, activated as a result of autocrine TGF-alpha expression in tumor cells, constitutively activates Stat3 [100]. Blocking Stat3 in vivo is associated with decreased level of the antiapoptotic Bcl-XL and increased tumor cell death [101]."

"Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation."

"These results indicate that Pyk2 facilitates EGFR- and c-Src-mediated Stat3 activation, thereby implicating Pyk2 activation as a potential co-mediator in triggering Stat3-induced oncogenesis."

"In vivo, b4-integrin amplifies proproliferative signals in basal epidermal keratinocytes (Nikolopoulos et al., 2005), where STAT3 is expressed and can be activated by EGF/EGF-R (Nishio et al., 2001; Chan et al., 2004; Li et al., 2007)"

"To explore this further, we have blocked endogenous ErbB3 transcription, thereby engineering tumor cells with overexpressed, fully active ErbB2 but lacking ErbB3 (T. Holbro and N.E. Hynes, unpublished data). As a consequence, these cells have decreased PI-3K/PKB signaling, a reduction in D-type cyclin levels, and show an increase in the G1 phase of the cell cycle. A main effector of ErbB signaling, the PI-3K/PKB pathway, is particularly important in mediating cell survival 103 T. Holbro et al. / Experimental Cell Research 284 (2003) 99-110 since several PKB substrates directly control various apoptotic processes. The proapoptotic Bcl family member Bad, when phosphorylated by PKB [93], is retained in the cytosol where it is unable to inhibit survival proteins like Bcl-XL on the mitochondria [94]. In normal mammary cells, blocking ErbB1 activity leads to apoptosis by lowering phospho-Bad levels, [95], a characteristic that would be extremely desirable to retain in cancer cells. Another PKB target is caspase-9, whose activation is blocked by phosphorylation [96] Members of the forkhead family of transcription factors, when phosphorylated by PKB, are retained in the cytoplasm and are unable to stimulate expression of several critical genes for apoptosis, including FasL, BIM, and others (reviewed by Brunet et al. [97]). Moreover, PKB phosphorylates IKK-alpha, which in turn inactivates IkappaB, thus leading to activation of NF-kappaB. This transcription factor upregulates levels of the prosurvival Bcl-XL protein and several inhibitors of apoptosis (IAPs) (reviewed by Datta et al. [98]). In this regard, it has been reported that cell lines overexpressing ErbB2 are resistant to TNF-induced apoptosis through a PKB/NF-B pathway [99]. Another ErbB effector protein, signal transducer, and activator of transcription (Stat) has been implicated in survival of squamous cell carcinomas of the head and neck. ErbB1, activated as a result of autocrine TGF-alpha expression in tumor cells, constitutively activates Stat3 [100]. Blocking Stat3 in vivo is associated with decreased level of the antiapoptotic Bcl-XL and increased tumor cell death [101]."

"These results indicate that Pyk2 facilitates EGFR- and c-Src-mediated Stat3 activation, thereby implicating Pyk2 activation as a potential co-mediator in triggering Stat3-induced oncogenesis."

"In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. See figure 2: The bow-tie architecture of the EGFR signaling pathway."

"Modified assertion"

"With respect to pre-EMT carcinoma cells, STAT3 is predominantly activated by the binding of EGF to EGFR (i.e., EGF dependent; XREF_FIG, left), and to a lesser extent, by the binding of FN to a complex comprised of alphavbeta3 integrin and EGFR (i.e., EGF independent; XREF_FIG, middle)."

"The binding of EGF to EGFR leads to an activation of Stat3 and subsequently a Stat3 induced increased expression of TWIST [XREF_BIBR]."

"Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min."

"Co-immunoprecipitation confirmed that EGFR and EPHB3 bind to each other and this binding increases upon resistance acquisition, suggesting that STAT3 is activated by the binding between EGFR and EPHB3."

"Although no direct binding data have been published, STATs have been proposed to couple to EGFR through tyrosine-1068 and tyrosine-1086 ?REF. 137?."

"EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models."

"In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. See figure 2: The bow-tie architecture of the EGFR signaling pathway."

"Overexpression of exogenous EGFR increased REP1 levels and STAT3 activation initially."