EGFR Signaling Pathway

Introduction

Epidermal growth factor (EGF) was first discovered in newborn rats in 1962. After about 20 years, the human epidermal growth factor receptor (EGFR) was isolated and purified. As research progresses, EGFR and its downstream pathways are constantly understood. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB, also known as Akt) signaling pathway is a downstream pathway of EGFR that is dysregulated in most human tumors. EGFR mainly stimulates the Ras protein after dimerization, which leads to the phosphorylation cascade and activates the PI3K/Akt signaling pathway, which causes tumorigenesis and development. Therefore, some scholars call it EGFR/PI3K/Akt signaling pathway. It has been confirmed that there are abnormal expression and dysfunction of EGFR in various malignant tumor tissues and tumor cell lines, including bladder cancer, ovarian cancer, nasopharyngeal carcinoma, breast cancer, glioblastoma, pancreatic cancer, prostate cancer, esophageal cancer and so on.

Studies have found that inactivation of PTEN inevitably leads to activation of the PI3K/Akt pathway, which is also the result of EGFR overexpression or mutation. Moreover, activated Akt has a variety of biological activities, which can promote the growth and proliferation of tumor cells through cascade phosphorylation of a series of proteins. It can also inhibit apoptosis, promote invasion and metastasis, regulate tumor angiogenesis, and tolerate tumor treatment. It can be seen that the dysregulation of EGFR/PI3K/ Akt signaling pathway is closely related to the occurrence and development of tumors.

Figure 1. An overview of the EGFR pathway and its main downstream effectors, PI3K/AKT and KRAS/BRAF/MEK/MERK

EGFR Pathway

The EGFR family is widely distributed in epithelial cell membranes, and its family members include EGFR (ErbB1 / HER-1), HER-2 (ErbB2), HER-3 (ErbB3), and HER-4 (ErbB4). The EGFR family is a transmembrane protein receptor with tyrosine kinase activity, which can be divided into three parts: extracellular region, transmembrane region, and intracellular region. Ligands (such as EGF, etc.) bind to the extracellular domain of EGFR and mediate EGFR dimerization via the ligand itself to form homologous or heterologous dimers. The autophosphorylation of the receptor is then effected in the dimer to activate the tyrosine kinase receptor (RTK). RTK triggers activation of a series of downstream signal transduction pathways, such as the Ras/Raf/MEK/ERK-MAPK pathway and the PI3K/Akt/mTOR pathway. Eventually, it acts on transcription factors, leading to tumor cell proliferation, infiltration, metastasis, and inhibition of tumor cell apoptosis and promotion of tumor cell angiogenesis.

In the EGFR family, EGFR and HER-4 are fully structured tyrosine kinase receptors. HER-2 has no direct ligand. EGFR, HER-3, and HER-4 preferentially bind to HER-2 to form a heterodimer when forming a heterodimer and simultaneously activate HER-2. In addition, since the extracellular region II and IV of HER-2 are rich in cysteine, homodimers can also be formed. Moreover, the heterodimer formed by HER-2 has stronger signal transduction function and receptor activity than the homodimer. HER-3 lacks intrinsic tyrosine kinase activity and acts by forming heterodimers with EGFR, HER-2, and HER-4. And HER-2, HER-3 heterodimers are the most important. There may be complex interactions between members of the EGFR family that affect the activity of the signal transduction pathway.

Downstream signaling of EGFR

The PI3K/AKT signaling pathway is the primary pathway for cancer cell survival and is a classical pathway for downstream signal transduction of EGFR. It plays an important role in the malignant transformation of cells and is known as the "anti-apoptotic pathway". Excessive activation of the signaling pathway leads to tumor formation and reduces the host's ability to defend against tumors.

The positive regulation of the EGFR/PI3K/Akt signaling pathway includes two forms: (1) After the ligand activation of EGFR, the adaptor protein Gab1 is phosphorylated. And as a core protein, a large number of downstream proteins, especially PI3K, are recruited. The C-terminal specific tyrosine phosphorylation of Gab1 binds to p85 of the PI3K regulatory subunit, resulting in a large accumulation of PI3K around Gab1. The N-terminal PH domain can bind to PIP3 on the cell membrane, causing a large amount of Gab1 to accumulate on the cell membrane, thereby increasing signal transmission. (2) When there is no Gab1, EGFR can only activate PI3K by forming a dimer with HER3. Activated PI3K in this pathway further catalyzes the production of PIP3 on the plasma membrane, which binds to the signal domain Akt containing the PH domain to activate Akt. Akt can also activate the expression of its downstream target protein, mTOR, by phosphorylation. After mTOR phosphorylation, it activates its direct substrate P70S6K, which accelerates cell protein synthesis and cell growth, further accelerating the progression of tumor progression.

The negative regulation of the EGFR/PI3K/Akt signaling pathway is largely dependent on the regulation of the tumor suppressor PTEN. PTEN is a new tumor suppressor gene recently discovered and is considered to be the most important tumor suppressor gene after p53. Its gene product has a strong catalytic effect on substrates having lipid phosphatase activity and protein phosphatase activity. PTEN can degrade the substrate PIP3 dephosphorylation into PIP2 and degrade it, blocking the activation of Akt and its downstream related target proteins. In addition, studies have shown that phosphatase can regulate the phosphorylation of the p85 subunit and inhibit the activation of PI3K, thereby blocking signal transmission.

The Ras /Raf/MEK/ERK signaling pathway plays a major downstream cell cycle regulatory role in the mitotic pathway and is another major pathway for downstream signaling of EGFR. As an important signal transduction pathway in ovarian cancer, Ras-Raf-MEK-ERK signal transduction cascade can be activated by a series of growth factors, which is closely related to the occurrence and development of tumors.

The presence of a large number of cytokines in the microenvironment surrounding ovarian cancer tissue can lead to the activation of EGFR, which triggers the activation of the Ras/Raf/MEK/ERK pathway and affects the cell cycle in tumor development. Studies have shown that the Ras/Raf/MEK/ERK signal transduction pathway plays a very important role in cell proliferation and survival. The relationship with tumors can be summarized as inhibition of tumor cell apoptosis, promotion of tumor angiogenesis, enhancement of tumor cell invasion and metastasis, etc.

EGFR and cancer

The role of EGFR in the formation of hepatocellular carcinoma (HCC). The EGFR signal is liver protection in the case of liver damage caused by diethylnitrosamine (DEN). In the absence of EGFR, hepatocytes undergo more necrosis and apoptosis, resulting in increased production of IL-1β, which stimulates the release of IL-6 by KuffER cells and is necessary to compensate for proliferation and repair of damaged hepatocytes. IL-1β-induced IL-6 production in Kupffer cells is dependent on EGFR expression. This includes activation of the IL-1R/MyD88 pathway to first induce EGFR ligand and ADAM17 expression, followed by EGFR transactivation required for IL-6 production by c-Jun N-terminal K.

Figure 2. EGFR function in hepatocytes

The EGFR/PI3K/Akt signaling pathway is essential in various aspects of tumor invasion and metastasis. The epithelial mesenchymal transition (EMT) is used to regulate the adhesion between cells so that epithelial cells have fibroblast-like properties. Furthermore, it enhances the ability of human salivary adenoid cell carcinoma cell line ACC cells to move in vivo and accelerate tumor metastasis. Studies have shown that by inhibiting the regulation of Akt1, the migration of mouse embryonic fibroblasts is impaired, and up-regulation of Akt1 expression restores cell migration.

In the retinal pigment epithelium (RPE), EGF can mediate its receptor EGFR and promote the migration of RPE cell line ARPE-19 cells through phosphorylation of PI3K/Akt pathway. After the application of EGFR and PI3K inhibitors, the invasion and metastasis ability of ARPE-19 is inhibited. Studies have shown that HER-3 is associated with poor prognosis of gastric adenocarcinoma. The researchers used PCR and immunohistochemistry to detect 161 cases of gastric cancer after the operation and in vitro cultured gastric cancer cell lines MKN45 and SGC-7901. HER-3 is found to promote the proliferation, survival and metastasis of gastric cancer cells by mediating the PI3K/Akt signaling pathway. It also shows that high expression of HER-3 is closely related to poor prognosis.

References:

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