Question

Discuss the EGF-activated signal transduction pathway and include details of cancer that can result from defects in this pathwa

Answer 1

Discuss the EGF-activated signal transduction pathway and include details of cancer that can result from defects in this pathway:

Epidermal growth factor receptor (EGFR) is the member of receptor tyrosine kinase family (RTK) of receptors which mediate various cellular activities, including cell proliferation, cell survival, growth and development.

EGFR receptors & ligands

Receptor - ligands

• EGFR - EGF, Transforming growth factor-α (TGF-α), Amphiregulin (AR), Betacellulin (BTC), Heparin-binding epidermal growth factor (HB-EGF) and Epiregulin (EPR)
• ErbB2 - None
• ErbB3 - NRG-1 and NRG-2
• ErbB4 - Betacellulin (BTC), Heparin-binding EGF-like growth factor (HB-EGF), Epiregulin (EPR), Tomoregulin, NRG-1, NRG2, NRG3 and NRG4

Cascade of receptor activation involves: Ligand binding- to cognate ErbB receptors; Receptor dimerization - formation of receptor homo or hetero dimers; Activation of kinase domain- Autophosphorylation of key tyrosine residues within carboxy terminal tail activates the receptor

• Ras/Raf signaling cascade:- Receptors: Dimerization of any two ErbB receptors
• Phosphatidylinositol 3-kinase/Akt signaling cascade:- Receptors:- Dimerization of ErbB2 with either ErbB4 or ErbB3
• Signal transducers and activators of transcription (STAT) pathway:- Receptors: ErbB
• Phospholipase Cγ signaling:- Receptors: ErbB1
• Nck/PAK signaling cascade:- Receptors: ErbB1
• Cbl mediated endocytosis:- Receptors: ErbB1

EGFR influence is widely observed in various cancers such as non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. EGFR aberrations trigger downstream pro-oncogenic signaling pathways such as: RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways which are observed to promote chronic and cell cycle progressed cell proliferation.