Special Issue "Epidermal Growth Factor Receptor Signaling"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling and Regulated Cell Death".

Deadline for manuscript submissions: 30 June 2019

Special Issue Editor

Guest Editor
Prof. Zhixiang Wang

Signal Transduction Research Group, Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
Website | E-Mail
Phone: +1-780-492-0710
Fax: +1-780-492-1998
Interests: ErbB receptors; cell signaling; protein trafficking; breast cancer; small GTPases and cell cycle

Special Issue Information

Dear Colleagues,

The epidermal growth factor receptor (EGFR), like other receptor tyrosine kinases (RTKs), regulates key events in cell growth, differentiation, survival and migration. Aberrant signaling from EGFR has been implicated in many diseases. EGFR is historically the prototypical RTK. It was the first of this large family of transmembrane receptors to be cloned, and the first for which a clear connection between aberrant receptor function and cancer could be drawn.

There are four members in the ErbB receptor family, also known as the EGFR family or type I receptor family, including EGFR or ErbB1/Her1, ErbB2/Her2, ErbB3/Her3 and ErbB4/Her4. The ErbB receptor family is unique among various groups of RTKs in that ErbB3 has impaired kinase activity, while ErbB2 does not have a direct ligand. Therefore, heterodimerization is an important mechanism that allows the activation of all ErbB receptors in response to ligand stimulation. The activated ErbB receptors bind to many signaling proteins and stimulate the activation of many signaling pathways, including the Ras-Raf-Mek-ERK, PI3K-Akt-Tor, PLC-γ1, STAT and Src pathways. The specificity and potency of intracellular signaling pathways are determined by positive and negative regulators, the specific composition of activating ligand(s), receptor dimer components, and the diverse range of proteins that associate with the tyrosine phosphorylated C-terminal domain of the ErbB receptors. Through the control of these diverse signaling networks, ErbB receptors regulate many critical cellular processes, such as cell proliferation, cell differentiation, cell survival, cell metabolism, cell migration, and cell cycle. Binding of EGF to EGFR also stimulates the rapid internalization of EGFR. EGFR endocytosis and EGFR-mediated cell signaling are mutually regulated.

In spite of significant advances in our understanding of EGFR signaling and trafficking, some critical knowledge is still lacking. Novel signaling pathways and cell functions are continuously identified as regulated by EGFR family. EGFR family receptor are still intensively explored for developing novel therapies targeting various cancers. This Special Issue will cover the recent progress in all of the areas related to EGFR family signaling and cancer.

Prof. Zhixiang Wang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • EGFR
  • ErbB receptor
  • cell signaling
  • trafficking
  • cell cycle
  • cancer
  • targeted cancer therapy

Published Papers (9 papers)

View options order results:
result details:
Displaying articles 1-9
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle
Regulation of EGFR Endocytosis by CBL During Mitosis
Cells 2018, 7(12), 257; https://doi.org/10.3390/cells7120257
Received: 1 November 2018 / Revised: 28 November 2018 / Accepted: 4 December 2018 / Published: 7 December 2018
Cited by 2 | PDF Full-text (6636 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The overactivation of epidermal growth factor (EGF) receptor (EGFR) is implicated in various cancers. Endocytosis plays an important role in EGFR-mediated cell signaling. We previously found that EGFR endocytosis during mitosis is mediated differently from interphase. While the regulation of EGFR endocytosis in [...] Read more.
The overactivation of epidermal growth factor (EGF) receptor (EGFR) is implicated in various cancers. Endocytosis plays an important role in EGFR-mediated cell signaling. We previously found that EGFR endocytosis during mitosis is mediated differently from interphase. While the regulation of EGFR endocytosis in interphase is well understood, little is known regarding the regulation of EGFR endocytosis during mitosis. Here, we found that contrary to interphase cells, mitotic EGFR endocytosis is more reliant on the activation of the E3 ligase CBL. By transfecting HeLa, MCF-7, and 293T cells with CBL siRNA or dominant-negative 70z-CBL, we found that at high EGF doses, CBL is required for EGFR endocytosis in mitotic cells, but not in interphase cells. In addition, the endocytosis of mutant EGFR Y1045F-YFP (mutation at the direct CBL binding site) is strongly delayed. The endocytosis of truncated EGFR Δ1044-YFP that does not bind to CBL is completely inhibited in mitosis. Moreover, EGF induces stronger ubiquitination of mitotic EGFR than interphase EGFR, and mitotic EGFR is trafficked to lysosomes for degradation. Furthermore, we showed that, different from interphase, low doses of EGF still stimulate EGFR endocytosis by non-clathrin mediated endocytosis (NCE) in mitosis. Contrary to interphase, CBL and the CBL-binding regions of EGFR are required for mitotic EGFR endocytosis at low doses. This is due to the mitotic ubiquitination of the EGFR even at low EGF doses. We conclude that mitotic EGFR endocytosis exclusively proceeds through CBL-mediated NCE. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessArticle
PET Imaging Biomarkers of Anti-EGFR Immunotherapy in Esophageal Squamous Cell Carcinoma Models
Cells 2018, 7(11), 187; https://doi.org/10.3390/cells7110187
Received: 10 October 2018 / Revised: 24 October 2018 / Accepted: 26 October 2018 / Published: 27 October 2018
PDF Full-text (3605 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Epidermal growth factor receptor (EGFR) is overexpressed and considered as a proper molecular target for diagnosis and targeted therapy of esophageal squamous cell carcinoma (ESCC). This study evaluated the usefulness of PET imaging biomarkers with 64Cu-PCTA-cetuximab and 18F-FDG-PET for anti-EGFR immunotherapy [...] Read more.
Epidermal growth factor receptor (EGFR) is overexpressed and considered as a proper molecular target for diagnosis and targeted therapy of esophageal squamous cell carcinoma (ESCC). This study evaluated the usefulness of PET imaging biomarkers with 64Cu-PCTA-cetuximab and 18F-FDG-PET for anti-EGFR immunotherapy in ESCC models. In vivo EGFR status and glucose metabolism by cetuximab treatment were evaluated using 64Cu-PCTA-cetuximab and 18F-FDG-PET, respectively. Therapeutic responses with imaging biomarkers were confirmed by western blot and immunohistochemistry. TE-4 and TE-8 tumors were clearly visualized by 64Cu-PCTA-cetuximab, and EGFR expression on TE-8 tumors showed 2.6-fold higher uptake than TE-4. Tumor volumes were markedly reduced by cetuximab in TE-8 tumor (92.5 ± 5.9%), but TE-4 tumors were refractory to cetuximab treatment. The SUVs in 64Cu-PCTA-cetuximab and 18F-FDG-PET images were statistically significantly reduced by cetuximab treatment in TE-8 but not in TE-4. 64Cu-PCTA-cetuximab and 18F-FDG-PET images were well correlated with EGFR and pAkt levels. 64Cu-PCTA-cetuximab immuno-PET had a potential for determining EGFR level and monitoring therapeutic response by anti-EGFR therapy. 18F-FDG-PET was also attractive for monitoring efficacy of anti-EGFR therapy. In conclusion, PET imaging biomarkers may be useful for selecting patients that express target molecules and for monitoring therapeutic efficacy of EGFR-targeted therapy in ESCC patients. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Graphical abstract

Open AccessArticle
Characterization and Drug Sensitivity of a New High-Grade Myxofibrosarcoma Cell Line
Cells 2018, 7(11), 186; https://doi.org/10.3390/cells7110186
Received: 24 July 2018 / Revised: 19 October 2018 / Accepted: 23 October 2018 / Published: 25 October 2018
Cited by 1 | PDF Full-text (4078 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Myxofibrosarcoma (MFS) belongs to the group of sarcoma tumors, which represent only 1% of the totality of adult tumors worldwide. Thus, given the rare nature of this cancer, this makes the availability of MFS cell lines difficult. In an attempt to partially fill [...] Read more.
Myxofibrosarcoma (MFS) belongs to the group of sarcoma tumors, which represent only 1% of the totality of adult tumors worldwide. Thus, given the rare nature of this cancer, this makes the availability of MFS cell lines difficult. In an attempt to partially fill this gap, we immortalized a primary culture of MFS (IM-MFS-1) and compared the cell morphology with patient’s tumor tissue. IM-MFS-1 was genetically characterized through a Comparative Genomic Hybridization (CGH) array and the mesenchymal phenotype was evaluated using Polymerase chain reaction (PCR) and immunofluorescence staining. Drug sensitivity for MFS therapies was monitored over time in cultures. We confirmed the conservation of the patient’s tumor cell morphology and of the mesenchymal phenotype. Conversely, the synthesis and expression of CD109, a TGFβ co-receptor used to facilitate the diagnosis of high-grade MFS diagnosis, was maintained constant until high cancer cell line passages. The CGH array revealed a complex karyotype with cytogenetic alterations that include chromosome regions associated with genes involved in tumor processes. Cytotoxicity assays show drug sensitivity constantly increased during the culture passages until a plateau was reached. In conclusion, we established and characterized a new MFS cell line that can be used for future preclinical and molecular studies on soft tissue sarcomas. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessFeature PaperArticle
Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs
Cells 2018, 7(10), 164; https://doi.org/10.3390/cells7100164
Received: 1 September 2018 / Revised: 23 September 2018 / Accepted: 8 October 2018 / Published: 11 October 2018
Cited by 1 | PDF Full-text (1621 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be [...] Read more.
Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessArticle
Preclinical Evaluation of [68Ga]Ga-DFO-ZEGFR:2377: A Promising Affibody-Based Probe for Noninvasive PET Imaging of EGFR Expression in Tumors
Received: 21 August 2018 / Revised: 13 September 2018 / Accepted: 15 September 2018 / Published: 18 September 2018
Cited by 1 | PDF Full-text (2232 KB) | HTML Full-text | XML Full-text
Abstract
Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this [...] Read more.
Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide 68Ga. Stability, specificity of binding to EGFR-expressing cells, and processing of [68Ga]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [68Ga]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [89Zr]Zr-DFO-ZEGFR:2377. DFO-ZEGFR:2377 was efficiently (isolated yield of 73 ± 3%) and stably labeled with 68Ga. Binding of [68Ga]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [68Ga]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [89Zr]Zr-DFO-ZEGFR:2377, [68Ga]Ga-DFO-ZEGFR:2377 demonstrated significantly (p < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [68Ga]Ga-DFO-ZEGFR:2377. In conclusion, [68Ga]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Graphical abstract

Review

Jump to: Research

Open AccessReview
Grb7, a Critical Mediator of EGFR/ErbB Signaling, in Cancer Development and as a Potential Therapeutic Target
Received: 30 March 2019 / Revised: 2 May 2019 / Accepted: 9 May 2019 / Published: 10 May 2019
PDF Full-text (789 KB) | HTML Full-text | XML Full-text
Abstract
The partner of activated epidermal growth factor receptor (EGFR), growth factor receptor bound protein-7 (Grb7), a functionally multidomain adaptor protein, has been demonstrated to be a pivotal regulator for varied physiological and pathological processes by interacting with phospho-tyrosine-related signaling molecules to affect the [...] Read more.
The partner of activated epidermal growth factor receptor (EGFR), growth factor receptor bound protein-7 (Grb7), a functionally multidomain adaptor protein, has been demonstrated to be a pivotal regulator for varied physiological and pathological processes by interacting with phospho-tyrosine-related signaling molecules to affect the transmission through a number of signaling pathways. In particular, critical roles of Grb7 in erythroblastic leukemia viral oncogene homolog (ERBB) family-mediated cancer development and malignancy have been intensively evaluated. The overexpression of Grb7 or the coamplification/cooverexpression of Grb7 and members of the ERBB family play essential roles in advanced human cancers and are associated with decreased survival and recurrence of cancers, emphasizing Grb7′s value as a prognostic marker and a therapeutic target. Peptide inhibitors of Grb7 are being tested in preclinical trials for their possible therapeutic effects. Here, we review the molecular, functional, and clinical aspects of Grb7 in ERBB family-mediated cancer development and malignancy with the aim to reveal alternative and effective therapeutic strategies. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessReview
Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators as a Therapy for Glioblastoma
Received: 27 March 2019 / Revised: 8 April 2019 / Accepted: 12 April 2019 / Published: 12 April 2019
PDF Full-text (989 KB) | HTML Full-text | XML Full-text
Abstract
Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. The biological function of epidermal growth factor receptor (EGFR) in tumorigenesis and progression has been established in various [...] Read more.
Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. The biological function of epidermal growth factor receptor (EGFR) in tumorigenesis and progression has been established in various types of cancers, since it is overexpressed, mutated, or dysregulated. Its overexpression has been shown to be associated with enhanced metastatic potential in glioblastoma, with EGFR at the top of a downstream signaling cascade that controls basic functional properties of glioblastoma cells such as survival, cell proliferation, and migration. Thus, EGFR is considered as an important therapeutic target in glioblastoma. Many anti-EGFR therapies have been investigated both in vivo and in vitro, making their way to clinical studies. However, in clinical trials, the potential efficacy of anti-EGFR therapies is low, primarily because of chemoresistance. Currently, a range of epigenetic drugs including histone deacetylase (HDAC) inhibitors, DNA methylation and histone inhibitors, microRNA, and different types of EGFR inhibitor molecules are being actively investigated in glioblastoma patients as therapeutic strategies. Here, we describe recent knowledge on the signaling pathways mediated by EGFR/EGFR variant III (EGFRvIII) with regard to current therapeutic strategies to target EGFR/EGFRvIII amplified glioblastoma. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessReview
Post-Translational Modification and Subcellular Distribution of Rac1: An Update
Cells 2018, 7(12), 263; https://doi.org/10.3390/cells7120263
Received: 13 November 2018 / Revised: 6 December 2018 / Accepted: 10 December 2018 / Published: 11 December 2018
Cited by 1 | PDF Full-text (1364 KB) | HTML Full-text | XML Full-text
Abstract
Rac1 is a small GTPase that belongs to the Rho family. The Rho family of small GTPases is a subfamily of the Ras superfamily. The Rho family of GTPases mediate a plethora of cellular effects, including regulation of cytoarchitecture, cell size, cell adhesion, [...] Read more.
Rac1 is a small GTPase that belongs to the Rho family. The Rho family of small GTPases is a subfamily of the Ras superfamily. The Rho family of GTPases mediate a plethora of cellular effects, including regulation of cytoarchitecture, cell size, cell adhesion, cell polarity, cell motility, proliferation, apoptosis/survival, and membrane trafficking. The cycling of Rac1 between the GTP (guanosine triphosphate)- and GDP (guanosine diphosphate)-bound states is essential for effective signal flow to elicit downstream biological functions. The cycle between inactive and active forms is controlled by three classes of regulatory proteins: Guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine-nucleotide-dissociation inhibitors (GDIs). Other modifications include RNA splicing and microRNAs; various post-translational modifications have also been shown to regulate the activity and function of Rac1. The reported post-translational modifications include lipidation, ubiquitination, phosphorylation, and adenylylation, which have all been shown to play important roles in the regulation of Rac1 and other Rho GTPases. Moreover, the Rac1 activity and function are regulated by its subcellular distribution and translocation. This review focused on the most recent progress in Rac1 research, especially in the area of post-translational modification and subcellular distribution and translocation. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Figure 1

Open AccessReview
Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy
Cells 2018, 7(11), 212; https://doi.org/10.3390/cells7110212
Received: 25 October 2018 / Revised: 13 November 2018 / Accepted: 15 November 2018 / Published: 15 November 2018
Cited by 3 | PDF Full-text (1027 KB) | HTML Full-text | XML Full-text
Abstract
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR [...] Read more.
Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial–mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs. Full article
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
Figures

Graphical abstract

Cells EISSN 2073-4409 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top