EGFR (Epidermal Growth Factor Receptor)
Recommended reading: 【Biology】 Chapter 1-3. Biopolymer Library
1. Overview
2. Yang et al.
1. Overview
⑴ EGFR/HER1 is translated as a 1210 aa precursor, after which the approximately 24 aa signal peptide at the N-terminus is removed, resulting in a mature protein of 1186 aa
⑵ EGFR structure
① Component 1. EGFR
○ Also called ErbB1 or HER-1
○ Structure: 170 kDa glycoprotein
○ Of this, the protein consists of a single polypeptide composed of 1186 amino acids
○ The initial precursor consists of a single polypeptide composed of 1210 amino acids
○ 60 to 80% of colorectal cancers overexpress EGFR
② Component 2. EGF
○ Structure: 6 kDa. Human EGF consists of 53 amino acids
○ 1 is the N-terminus and 1210 is the C-terminus, and the N-terminus is the part protruding outside the cell
○ The region 645-666, which has a high hydrophobicity index value, is the TM (transmembrane) helix region
Figure 1. EGFR hydrophobicity index
Figure 2. EGFR PTM pattern
⑶ EGFR signaling pathway
① 1st. When EGF and EGFR bind, they induce a structural change, activating TKD
② 2nd. The following kinds of signaling proteins bind to phosphorylated EGFR
○ Type 1. SH2(src homology-2): The amino terminus of SH2 recognizes the tyrosine sequence
○ Type 2. Shc PTB(phosphotyrosine binding) domain: The carboxyl terminus of the PTB domain binds
③ 3rd. Major downstream signaling
○ Ras → Raf → ERK
○ PI3K → Akt → mTOR
Figure 3. EGFR signaling pathway
④ Positive feedback regulators
○ ERBB ligands: TGFα, HB-EGF, etc. show increased expression after the above signaling pathway
⑤ Negative feedback regulators
○ DEP(density-enhanced phosphatase-1)
○ SOCS5(cytokine signaling-5)
⑷ EGFR-targeted small-molecule drugs
① gefitinib (Iressa): An anticancer drug that inhibits EGFR-TKI(EGFR-tyrosine kinase inhibitor). FDA-approved
② erlotinib (Tarceva)
⑤ lapatinib (Tyverb): Inhibits TKD to directly suppress downstream signalling. FDA approved
⑥ afatinib (BIBW2992): Inhibits the tyrosine-kinase domain to directly suppress downstream signalling. FDA approved
⑦ sapitinib
⑧ canertinib
⑨ osimertinib (Tagrisso)
⑸ EGFR-targeted antibody drugs
① Overview: Mainly domain III becomes the antibody target (e.g. petosemtamab, 7D12)
Figure 4. EGFR domain
○ Based on the 1186 aa mature protein, domain III is 310-480 aa
○ Based on the 1210 aa precursor, domain III is 334-504 aa
② cetuximab (Erbitux): FDA-approved
○ IgG1 isotype
○ binding site: Q384, Q408, H409, K443, K465, I467, S468, F352, D355, P387
○ Has immunogenic activity
③ panitumumab (Vectibix): FDA-approved
○ IgG2 isotype
○ binding site: P349, P362, D355, F412, I438
○ Has no immunogenic activity
④ nimotuzumab
⑤ 806
2.Yang et al.
⑴ CTX ―⊕→ resistance to CTX
① competitive binding of CTX to EGFR ―⊝→ EGF downstream signaling (in vitro)
② ↓ EGF downstream signaling ―⊕→ resistance to CTX
③ EGF downstream signaling = RAS/RAF/ERK + PI3K/AKT/mTOR
⑵ NDRG1 ―⊕→ sensitivity to CTX (in vitro, in vivo)
① NDRG1 ―ⓧ→ EGFR mRNA expression (in vitro)
③ NDRG1 ―⊝→ EGFR phosphorylation (in vitro)
⑤ NDRG1 ―⊝→ EGFR localization in the membrane, cytoplasm, and nucleus (in vitro, ref)
⑥ NDRG1 ―⊝→ EGFR lysosomal degradation and ubiquitination (in vitro, ref, ref)
⑶ Inference
① Inference 1. EGFR mRNA expression and protein expression are quite different
○ Reason: Because there is a difference in responsiveness according to NDRG1 gene perturbation
② Inference 2. EGFR protein expression ↑ ―⊕→ CTX ↑
③ Inference 3. CTX ―⊝→ NDRG1
○ Since CTX is a perturbation, it should be positioned upstream
○ Since NDRG1 is not a perturbation but a signaling mediator, it should be positioned at an intermediate stage
○ If CTX promotes NDRG1 expression, CTX sensitivity becomes ambiguous, so it is reasonable for it to suppress expression
④ Inference 4. If NDRG1 gene perturbation is added, CTX treatment becomes useless, so CTX sensitivity appears
⑤ Inference 5. In EGFR → CTX → NDRG1 → CTX resistance, there separately exists an NDRG1 ―⊝→ EGFR compensatory circuit
○ Since it is uncertain whether CTX-induced CTX resistance is related to EGFR, it is difficult to conclude that there is a CTX → EGFR compensatory circuit
Input: 2022.04.28 21:57
Revised: 2026.04.04 02:12