Epidermal Growth Factor Receptor (EGFR) Phosphorylation, Signaling and Trafficking in Prostate Cancer

Huang, Yao; Chang, Yongchang

doi:10.5772/27021

Cited by 16 publications

(33 citation statements)

References 166 publications

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“…Though in both cases, the EGF- stimulated and the Herbimycin A situation, fluorescence-based EGFR transphosphorylation detection revealed an in part grainy fluorescence pattern, possibly indicating endosomal receptor stages [11], the status of activity of the receptor can be different. While transphosphorylated receptor retains its signaling action in endosomes as well [58], Herbimycin A has been shown to support receptor ubiquitination and degradation [59]. Hence, ubiquitinated receptors are excluded from further action [11,20].…”

Section: Discussionmentioning

confidence: 98%

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors

Eberwein

Laird

Schulz

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Within the concept of integrin growth factor receptor (GFR) cross-talk, little is known about the effects of GFRs on focal adhesions (FAs). Therefore, we tested the hypothesis whether EGF can modulate constituents of FAs and subsequent down-stream events. To this end, EGF-treated keratinocytes were subjected to combined fluorescence imaging and western blotting, to quantify expression and/or activation of molecules, involved in integrin GFR cross-talk, and receptor proximal and distal signaling events. Generally, EGF response revealed an amplified redistribution or activation of molecules under study, which will be explained in detail from the plasma membrane to the cell interior. In addition to significant activation of EGF receptor (EGFR) at tyrosine Tyr845, a remarkable redistribution was detectable for the focal adhesion constituents, integrin ß1 and ß3, and zyxin. Increased activation also applied to focal adhesion kinase (FAK) by phosphorylation at Tyr397, Tyr576, and Src at Tyr418, while total FAK remained unchanged. Risen activity was seen as well for the analyzed distal down-stream events, p190RhoGAP and MAP kinases p42/44. Intriguingly, Src-specific inhibitor Herbimycin A abrogated the entire EGF response except FAK Tyr397 phosphorylation, independent of EGF presence. Mechanistically, our results show that EGF modulates adhesion in a dual fashion, by firstly redistributing focal adhesion constituents to adhesion sites, but also by amplifying levels of activated RhoA antagonist p190RhoGAP, important for cell motility. Further, the findings suggest that the observed EGF response underlies an EGFR integrin cross-talk under recruitment of receptor proximal FAK and Src, and MAP kinase and p190RhoGAP as receptor distal events.

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Section: Discussionmentioning

confidence: 98%

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors

Eberwein

Laird

Schulz

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…We hypothesize that this difference in the observed PPI patterns would stem from different biogeneses of EVs. EGFRs on plasma membrane, after transmitting the signal for a finite amount of time, are either i) transferred to microvesicles formed by direct outward budding of the membrane or ii) internalized by endocytosis, incorporated into endosomes, and finally loaded onto exosomes . Direct budding of the microvesicles from the plasma membrane may entail a higher functional similarity between the EGFRs in the microvesicles and the plasma membrane.…”

mentioning

confidence: 99%

Single‐Molecule Co‐Immunoprecipitation Reveals Functional Inheritance of EGFRs in Extracellular Vesicles

Sung

Jung

Jeong

et al. 2018

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Cancer cells actively release extracellular vesicles (EVs) as important carriers of cellular information to tumor microenvironments. Although the composition and quantity of the proteins contained in EVs are characterized, it remains unknown how these proteins in EVs are related to those in the original cells at the functional level. With epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells as a model oncoprotein, it is studied how distinct types of EVs, microvesicles and exosomes, represent their original cells at the protein and protein–protein interaction (PPI) level. Using the recently developed single‐molecule immunolabeling and co‐immunoprecipitation schemes, the quantity and PPI strengths of EGFRs derived from EVs and the original lung adenocarcinoma cells are determined. It is found that the microvesicles exhibit higher correlations with the original cells than the exosomes in terms of the EGFR levels and their PPI patterns. In spite of these detailed differences between the microvesicles and exosomes, the EGFR PPI strengths measured for EVs generally show a tight correlation with those determined for the original cells. The results suggest that EGFRs contained in EVs closely reflect the cellular EGFR in terms of their downstream signaling capacity.

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“…In step 4, in a D2-dependent fashion, E4-ORF1 triggers ligand-independent EGFR activation that stimulates Ras/Mek/ Erk signaling (Fig. 1A, B, and E and 2C), presumably by inducing EGFR autophosphorylation on tyrosine residues Y1068, Y1086, and/or Y1148, which is known to stimulate this pathway (45). Because E4-ORF1 interacts with only a small fraction of Dlg1: EGFR complexes in cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…2C and 6B to E). One possibility is that InsR/IGF1R induces EGFR phosphorylation on the inhibitory tyrosine residues Y992, Y1045, and/or Y1173, which suppress Erk1/2 signaling by recruiting cellular phosphatases or ubiquitin ligase to EGFR (45). Because an inhibitory factor(s) in conditioned medium may dampen EGFR activation and signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

Kong

Kumar

Taruishi

et al. 2015

J Virol

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The E4-ORF1 protein encoded by human adenovirus stimulates viral replication in human epithelial cells by binding and activating cellular phosphatidylinositol 3-kinase (PI3K) at the plasma membrane and cellular Myc in the nucleus. In this study, we showed that E4-ORF1 hijacks the tyrosine kinase activities of cellular epidermal growth factor receptor (EGFR) and insulin receptor (InsR)/insulin-like growth factor receptor 1 (IGF1R), as well as the lipid kinase activity of PI3K, to mediate constitutive Myc protein expression. We additionally demonstrated that EGFR contributes to constitutive Myc expression through the capacity of E4-ORF1 to induce ligand-independent EGFR activation and stimulation of the Ras/Mek/Erk pathway, the latter activity of which was conserved by human adenoviruses. Results further suggested that EGFR normally forms a complex with the cellular PDZ protein Discs Large 1 (Dlg1), a component of the Dlg1:E4-ORF1:PI3K ternary complex that mediates E4-ORF1-induced PI3K activation, and that E4-ORF1 binds the Dlg1:EGFR complex and promotes the association of EGFR with InsR and IGF1R. In addition to its role in constitutive Myc expression, InsR/IGF1R also negatively regulates EGFR autophosphorylation and EGFR-mediated Ras/Mek/Erk signaling, and data suggested that E4-ORF1 binding to Dlg1 antagonizes these activities. Collectively, our findings suggest that in human epithelial cells, E4-ORF1 targets EGFR, InsR/IGF1R, and PI3K at the plasma membrane to activate cytosolic signaling pathways that sustain Myc protein levels in the nucleus. We postulate that E4-ORF1-induced constitutive Myc expression functions to ensure the formation of nuclear E4-ORF1:Myc complexes, which have been shown to activate Myc and to enhance adenovirus replication. O ver 60 human adenovirus (Ad) serotypes are classified into seven subgroups (subgroups A through G) based on oncogenic, hemagglutination, and virion structural protein properties as well as genome sequence similarity (1). Ad is a human pathogen primarily associated with mild, self-limited respiratory diseases but additionally causes gastroenteritis, conjunctivitis, cystitis, and skin rashes (1). Certain viral serotypes, such as Ad type 14 (Ad14), can cause life-threatening symptoms that require hospitalization for up to 40% of otherwise healthy individuals (2), and Ad infections of neonates and immunosuppressed patients are associated with high morbidity and mortality rates (3). However, current treatments for severe Ad infections are controversial and carry significant risks for adverse events (1). Ad is also exploited as a vector for vaccination and gene and cancer therapy as well as a tool of discovery to reveal fundamental mechanisms of the cell and mechanisms for cancer development (1).The Ad early region 4 open reading frame 1 gene (E4-ORF1) encodes a 14-kDa protein required for optimal viral replication (4-6). In humans, subgroup D Ad9 is associated with eye infections (1), whereas Ad9 inoculation into experimental animals elicits estrogen-dependent m...

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Epidermal Growth Factor Receptor (EGFR) Phosphorylation, Signaling and Trafficking in Prostate Cancer

Cited by 16 publications

References 166 publications

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors

Single‐Molecule Co‐Immunoprecipitation Reveals Functional Inheritance of EGFRs in Extracellular Vesicles

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression

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