Introduction: The Critical Role of EGFR in Cell Communication

Balance in the human body requires the ability of cells to communicate with each other and respond promptly to environmental cues. At the core of this communication lies signal transduction, where a signal produced by an external stimulus is propagated from the cell surface to the nucleus through a signaling cascade.

The receptor tyrosine kinase (RTKs) family is integral to the commencement of signal transduction, as it comprises receptors that can bind external stimuli. Among the RTKs, the epidermal growth factor receptor (EGFR) stands out for the myriad signal transduction pathways it influences. Its main binding partners are cytokines and growth factors, small proteins secreted into the extracellular matrix (ECM). EGF receptor signaling pathways regulate fundamental cell fate decisions, including proliferation, differentiation and apoptosis.¹ Simultaneously, abnormalities in EGFR signaling contribute to cancer and many other diseases.²

What is the EGF Receptor Signaling Pathway?

The EGF Receptor Signaling Pathway is a signal transduction pathway that delivers external growth signals to transcription factors in the nucleus, orchestrating gene expression for cellular processes.¹

EGFR belongs to the ErbB family, which contains four structurally related RTKs, such as ErbB1 (EGFR), ErbB2, ErbB3 and ErbB4, all encoded by the viral oncogene ErbB.³ Each ErbB receptor consists of a ligand-binding ectodomain (extracellular) region, a transmembrane domain, and an intracellular cytoplasmic domain that interacts with other ErbBs and signaling cascades.³ Furthermore, ErbBs, including EGFR, form homodimers or heterodimers upon stimulation by a binding partner.⁴

The binding partners of EGFR include:

1. Epidermal Growth Factor (EGF): The most well-characterized EGFR ligand, responsible for epithelial tissue development¹
2. Transforming Growth Factor Alpha (TGF-α): involved in epithelial development and regeneration⁵
3. Amphiregulin: partaking in tissue repair and inflammation⁶
4. Betacellulin: involved in pancreatic beta-cell proliferation⁷
5. Heparin-binding EGF-like Growth Factor (HB-EGF) is essential in wound healing and cardiac development¹
6. Epiregulin, implicated in inflammatory responses and tissue regeneration⁸
7. Neuregulins (NRG1–NRG4), which contribute to nervous system development⁹

Collectively, these ligands bind EGFR, facilitating its dimerization and phosphorylation of the tyrosine residues in its intracellular domain.¹⁰

Mechanism of EGFR Activation

EGFR activation is initiated by the extracellular ligands, such as EGF or TGF-α, which bind to the EGFR extracellular domain. This binding induces a conformational change that facilitates dimerization by exposing the concealed dimerization sites when a monomeric EGFR is inactive.¹

EGFR can form a homodimer with another EGFR or a heterodimer with another ErbB.¹¹ In both cases, dimerization is necessary for activation at the intracellular tyrosine kinase domain.¹⁰ Dimerization is followed by autophosphorylation, in which two receptors phosphorylate each other's kinase domains in a process called trans-activation.¹²

EGFR phosphorylation occurs at specific tyrosine residues, converting them to docking platforms for adaptor proteins, which activate downstream signaling pathways. The growth factor receptor-bound protein 2 (GRB2) and Src Homology 2 domain-containing (Shc) transforming protein 1 are among the main binding partners of active EGFR.² These proteins can recruit Son of Sevenless (SOS), which activates Ras GTPase and initiates the following pathways:

1. Mitogen-activated protein kinase (MAPK) signaling pathway, where the signal is propagated across RAS-RAF-MEK-ERK proteins, and active ERK translocates to the nucleus to regulate gene expression.¹³
2. EGFR can also recruit phosphoinositide 3-kinase (PI3K), which activates protein kinase B (AKT). This, in turn, activates the mammalian target of rapamycin (mTOR), a protein that controls cell growth, proliferation, motility and survival.¹⁴
3. EGFR can activate phospholipase C gamma (PLCγ) to promote protein kinase C (PKC) activation. This pathway is critical for calcium signaling and cytoskeletal rearrangements.¹⁵
4. EGFR phosphorylates the signal transducer and activator of the transcription (STAT) family, such as STAT1 and STAT3, which mediate inflammation, immune response, proliferation and differentiation.¹⁶'¹⁷

EGFR Signal Regulation: Endocytosis, Trafficking and Degradation

The EGF receptor signaling pathways are tightly controlled by endocytosis, trafficking and degradation to maintain homeostasis and prevent aberrant signaling.¹⁸

The active EGFR-ligand complex is internalized through clathrin-dependent or independent endocytosis. The EGFR endosomes can be recycled back to the plasma membrane, where they resume signaling. On the other hand, it can get ubiquitinated and directed to the lysosome, which induces its degradation to attenuate signal transduction.¹⁹

Inside the cell, EGFR can also partake in crosstalks with the Wnt/β-catenin pathway, another signaling pathway critical in development and homeostasis. It can control gene expression by supporting β-catenin accumulation and nuclear translocation, establishing a balance between cell growth and differentiation.²⁰

Furthermore, EGFR can translocate to the nucleus to act as a transcription regulator by binding the promoter regions of genes, such as cyclin D1, to manage cell fate decisions.²¹

EGFR and Cytokine Signaling: Crosstalks in Inflammation and Cancer

There is a bidirectional relationship between cytokines and EGFR signaling pathways that governs essential processes like inflammation, repair and regeneration and promotes tumor development.²²

Research suggests that proinflammatory cytokines, such as interleukins IL-1 and IL-6 and tumor necrosis factor-alpha (TNF-α), could induce upregulation of EGFR expression.²² In addition, Cytokine receptors and EGFR could synergistically activate intracellular signaling pathways, although this convergence could enhance proliferation and survival in cancer cells. EGFR/JAK/STAT3 and IL6/STAT3 axes are such pathways that work together to over-activate the STAT signaling pathway.²³

In return, EGFR and downstream signaling pathways can amplify cytokine expression and secretion, engendering sustained signaling that underlies inflammatory diseases and cancer.²⁴ Many of the cytokines upregulated in cancer are associated with dysregulated immune checkpoints in immunosuppression. In contrast, upregulated chemokines act as chemoattractants that recruit neutrophils, tumor-associated macrophages (TAMs) and regulatory T cells.²⁵ Both cancer cells and TAMs continue to secrete cytokines that further activate EGFR-related pathways.²⁶ Thus, a pro-tumorigenic loop is created.

EGFR Signaling in Cancer and Disease

EGFR mutations, overexpression and overactivation are common hallmarks of various human cancers, driving uncontrolled proliferation, angiogenesis, metastasis and resistance to apoptosis.²

EGFR is overexpressed in many cancers, mainly in breast and colorectal tumors.¹² Furthermore, exon deletions and point mutations are often observed in non-small cell lung cancer (NSCLC) and glioblastoma, rendering EGFR constitutively active independently of ligand binding.¹²

EGFR's role in many cancers was uncovered through extensive research. Below are some examples:

1. In colorectal cancer, EGFR overexpression is more common than mutations.²⁷
2. EGFR is also frequently overexpressed in triple-negative breast cancer, with inhibitors displaying limited efficacy.²⁸
3. EGFR mutations are prevalent among non-smokers in NSCLC. In particular, T790M mutations, MET amplification and histological transformation are correlated with poor prognosis and resistance to EGFR inhibitors, such as erlotinib and gefitinib.²⁹'³¹
4. The type III EGFR mutation (EGFRvIII) is frequently observed in glioblastoma, where the mutant EGFR lacks the extracellular ligand-binding domain yet remains active. This type of glioblastoma has an aggressive phenotype associated with angiogenesis and therapy resistance.³²

EGFR overexpression and mutations generally lead to sustained activation of signal transduction pathways, downregulation of tumor suppressors and apoptotic pathways, crosstalk with other RTK-related pathways, immune evasion and metastasis.²

Applications in Drug Discovery and Diagnostics

The broad impact of EGFR on cancerous signaling pathways makes it an attractive target for drug development and cell therapy strategies.

To that end, tyrosine kinase inhibitors (such as gefitinib, erlotinib and Osimertinib) and monoclonal antibodies (such as cetuximab and panitumumab) were developed to inhibit EGFR.³³ These inhibitors block EGFR activation by interfering with EGFR ligand binding.³³ However, their success was hampered by the EGFR mutants that do not require ligand binding for activation.²⁹ Furthermore, the mutations in downstream pathway components, such as KRAS and BRAF, rendered EGFR inhibition ineffective.³⁴

Next-generation EGFR inhibitors that can bind EGFR mutants are under investigation to overcome these bottlenecks.³⁵ Furthermore, combination therapies co-targeting EGFR and downstream pathways, such as MAPK and PI3K/AKT, have the potential to inhibit the aberrant signal transduction systemically.³⁶'³⁷

Nevertheless, developing more robust EGFR therapies requires a thorough study of EGFR signaling in disease models. In vitro, in vivo and organoid models could reveal the mechanisms leading to EGFR mutation, drug resistance and heterogeneity in patient profiles, paving the way for more accurate patient stratification and personalized medicine.³⁸

Cellular assays and screening methods are central to developing accurate disease models. Cell-based assays and high-content imaging could be used to monitor EGFR dimerization and phosphorylation.³⁹ Furthermore, high-throughput screening can help identify small molecule inhibitors and guide the structural optimization of lead compounds, improving the chances of clinical success.⁴⁰

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