EGFR

Definition

Epidermal growth factor receptor (EGFR; ErbB-1; HER1) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. Epidermal growth factor receptor (EGFR) is a membrane surface protein with tyrosine kinase activity, commonly expressed in epidermal cells and stromal cells of the human body, and highly expressed in a variety of human tumor cells.The epidermal growth factor (EGF or ErbB) family is a pleiotropic cell surface signaling system. The family mainly includes four transmembrane receptors: human epidermal growth factor receptor 1 (EGFR), human epidermal growth factor receptor 2 (ErbB2), human epidermal growth factor receptor 3 (ErbB3) and human epidermal growth factor receptor 4 (ErbB4).

EGFR is a tyrosine kinase receptor (RTK) that is an expression product of the proto-oncogene c-ErbB1. Located on chromosome 7, it is composed of 28 exons, encoding 1 186 amino acids, and its glycoprotein has a relative molecular mass of about 170 000, consisting of 1 extracellular functional region (ECD) that can bind EGF, 1 short transmembrane region (TM) and 1 intracellular region with tyrosine kinase activity. Defects in signaling of epidermal growth factor receptors and other receptor tyrosine kinases in humans have been linked to diseases such as Alzheimer's disease, while overexpression has been linked to the development of multiple tumors. Epidermal growth factor receptor plays an important role in the occurrence and development of a series of malignant tumors, and has a certain regulatory effect on promoting tumor cell growth, cell proliferation, angiogenesis, tumor cell invasion, metastasis and apoptosis. The expression level of EGFR can be used as an indicator to judge the prognosis of various tumors.

Signaling Pathways of EGFR

The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation, and differentiation. There are three main ways in the EGFR signaling pathway.

--RAs/RAF/ERK Pathway: EGFR itself phosphorylates and directly or indirectly binds to the complex of growth factor receptor-binding protein Grb-2, activates Ras protein, and activated Ras activates downstream silk/threonine protein kinase Raf, thereby phosphorylating Erkl/2, transmitting signals to the nucleus, leading to phosphorylation of intranuclear transcription factors, initiating the transcription of target genes, and eventually leading to biological effects such as cell proliferation and diffusion.

--PI3K/AKT Pathway: phosphorylated EGFR binds to linker protein (Gab1) to activate the downstream phosphatidylinositol-3-kinase (PI3K), and then activates protein kinase B (PKB/AKT) and protein kinase C (PKC), and the activated PKB can participate in the RAS/RAF/ERK pathway to achieve the corresponding biological effects, and its own activation can also produce anti-apoptotic effects; Activated PKC induces phosphorylation of IkBα, which moves the nuclear factor kB (NF-kB) into the nucleus, thereby regulating the transcription of target genes.

--Ral/c-Src/STAT Pathway: EGFR can indirectly activate proto-oncogene protein (c-Src) by binding to Ral-GTPase, and the activated c-Src activates the downstream signal transcription activator (STAT) and activates the transcription of target genes.

Fig.1 EGFR Signaling Cascades

Function

The epidermal growth factor receptor (EGFR) is a transmembrane protein that is activated by binding to its specific ligands, including epidermal growth factor and transforming growth factor α (TGF-α). ErbB2 has no known direct-activating ligand and may be in a constitutely activated state or become active after heterodimerization with other family members such as EGFR.

EGFR dimerization stimulates its intrinsic intracellular protein tyrosine kinase activity. As a result, several tyrosine residues in the C-terminal domain of the EGFR undergo autophosphorylation. The kinase domain of EGFR can be cross-phosphorylated with tyrosine residues of other receptors it aggregates, thereby activating itself.

Fig. 2 Diagram of The EGF Receptor Highlighting Important Domains

Clinical Application

Cancer

Mutations that cause EGFR overexpression (called upregulation or amplification) are associated with many cancers, including lung adenocarcinoma (40% of cases), cancer, glioblastoma (50%), and head and neck epithelial tumors (80-100%). These somatic mutations involving EGFR lead to its sustained activation, resulting in uncontrolled cell division. In glioblastoma, specific mutations in EGFR, called EGFRvIII, are often observed. Mutations, amplifications, or dysregulation of EGFR or its family members are associated with epithelial carcinoma in approximately 30% of cases.

Inflammatory Diseases

Abnormal EGFR signaling is associated with psoriasis, eczema, and atherosclerosis.

Wound Healing and Fibrosis

EGFR has been shown to play a key role in TGF-β1-dependent fibroblast differentiation into myofibroblasts. The persistence of myofibroblasts abnormally within tissues can lead to progressive tissue fibrosis that impairs tissue or organ function (e.g., hypertrophic skin or keloids, cirrhosis, myocardial fibrosis, chronic kidney disease).

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