Lecture Seven: EGFR

The lecture aims to review the structure, function, and types of Epidermal Growth Factor Receptor (EGFR) and its respective ligands. There is an in-depth discussion of how the signaling pathway switches on and off, particularly on receptor activation, signal transduction, and cellular response. There are several ways in which the EGFR transduces the signal inside the cell via phosphatidylinositol-3 kinase PI3K/Akt/mTOR, JAK-STAT, phospholipase C (PLC-γ) gamma protein and protein kinase C (PKC) and this lecture focuses on Raf/Ras/MAPK/ERK. The crosstalk and link between GPCR and EGFR signaling pathways are discussed and involve members of the RAS family of proteins. Rap-1 and 2 are targets of Protein kinase A (PKA). One of the cAMP targets, Epac, guanosine exchange factor (GEF) stimulates Rap-1 and Rap-2. Protein kinase C and CREB also partake in both signaling pathways. Moreover, the causes of dysregulation of EGFR signaling pathways reviewed, for instance, mutations and overexpression of the EGFR receptor, EGF ligand, and downstream signaling protein (RAS, RAF, ERK, MEK, and protein kinase) that exacerbate many hallmarks of cancer.

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Structure Of The EGFR

The EGFR receptor glycoprotein is a member of the tyrosine kinase family. It consists of 1,186 amino acids and has three main domains: extracellular, transmembrane, and intracellular. The extracellular domain (ECD) is the N-terminal containing 621 amino acids. The ECD is divided further into four domains: parts I (orange) and III (pink) consist of leucine amino acid residues where the binding with the ligand occurs. Part II (aqua blue) consists of cysteine amino acid residues and the dimerization arm present to interact with another dimerization arm to form a dimer and facilitate EGFR signaling. Part IV (navy blue) has cysteine amino acid residues and forms disulfide bonds with part II to form the transmembrane domain. It does not make contact with the ligand.
The transmembrane domain consists of 23 amino acids. It is a hydrophobic region (water-hating) and attaches the receptor to the membrane and partakes in the dimerization process.
The intracellular domain (ICD) consists of tyrosine kinase domain (green) and the C-terminal (fuchsia pink) that faces the cytoplasm. It contains 542 amino acids, particularly tyrosine residues where phosphorylation occurs. The ICD has lysine residues involved in ubiquitination. A larger size of the image can be found in the resource list.

The EGFR signalling pathway

The image presents the three key steps involved in the EGFR signaling pathway. During receptor activation, the EGF protein ligands (grey diamond) bind with the EGFR receptor (orange). The dimerization arm of the extracellular domain II of one receptor with ECD II of another receptor forms a homodimer. Transautophosphorylation of the cytoplasmic domain (green) of the intracellular domain containing tyrosine residues of one EGFR phosphorylates the cytoplasmic domain of the other EGFR. The downstream signaling pathway involves the recruitment of six effector proteins. Growth factor receptor bound protein 2 (GRB2) adaptor protein (blue) binds to phosphorylation sites of EGFR. Son of sevenless (green; Sos) is the guanine nucleotide exchange factor that interacts with GRB2 at the plasma membrane (navy blue). Sos further interacts with a small guanosine triphosphatase enzyme called Ras (orange pink). Ras activates the downstream effector RAF-1, mitogen-activated protein kinase kinase-MAPKK (MEK). MAPK is translocated to the nucleus and phosphorylates the transcription factors such as cy-myc, Jun, and c-Fos to induce cellular response. A larger size of the image can be found in the resource list.