The epidermal growth factor receptor (EGFR) is a protein on the surface of human cells. It acts like an antenna, receiving specific signals from outside the cell. These signals, called growth factors, instruct the cell to perform various basic functions. EGFR’s proper functioning regulates many normal bodily processes, guiding cell life cycles and maintaining tissue health.
Understanding Epidermal Growth Factor Receptors
EGFR is a transmembrane protein, spanning the cell membrane. Its extracellular domain binds to specific signaling molecules like epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α).
When a growth factor attaches to the extracellular domain, it changes the receptor’s shape. This change affects the intracellular domain, located inside the cell’s cytoplasm. This intracellular part contains a tyrosine kinase domain, which adds phosphate groups to other proteins. This phosphorylation is the initial step in transmitting the external signal into the cell.
How EGFR Regulates Cell Processes
When a growth factor binds to EGFR’s extracellular portion, two EGFR molecules come together, forming a dimer. This dimerization activates the tyrosine kinase domain on the receptor’s intracellular side. The activated kinase then phosphorylates specific tyrosine residues on EGFR and other target proteins within the cell.
This phosphorylation initiates intracellular signaling pathways. Two pathways activated by EGFR are the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Activation of these pathways leads to changes in gene expression, influencing cellular activities such as:
- Promoting cell growth
- Stimulating cell division or proliferation
- Ensuring cell survival by inhibiting programmed cell death
- Guiding cell differentiation into specialized types
EGFR’s Link to Cancer Development
Dysregulation of EGFR signaling can contribute to the development and progression of various cancers. One primary mechanism involves activating mutations within the EGFR gene, particularly in the tyrosine kinase domain. These mutations, such as exon 19 deletions or the L858R point mutation in exon 21, lead to constitutive activation of the receptor, meaning it remains “on” even without a growth factor binding. This persistent activation drives uncontrolled cell growth and proliferation.
Another way EGFR contributes to cancer is through overexpression, where cancer cells produce an abnormally high number of EGFR proteins on their surface. This increased receptor density makes cells hypersensitive to even low levels of growth factors, leading to excessive signaling. Gene amplification, involving multiple copies of the EGFR gene, is often the cause of this overexpression. These abnormalities are observed in several cancer types, including non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck squamous cell carcinoma.
Therapeutic Strategies Targeting EGFR
Understanding EGFR’s role in cancer has led to the development of targeted therapies to block its abnormal activity. Two classes of drugs are used: tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. TKIs are small molecule drugs that enter the cell and bind to the ATP-binding site within the EGFR tyrosine kinase domain, preventing its activation. Examples include gefitinib, erlotinib, and osimertinib, which block downstream signaling pathways that drive cancer cell growth.
Monoclonal antibodies are larger protein drugs that work outside the cell. These antibodies bind to EGFR’s extracellular domain, physically blocking growth factors from attaching to the receptor. This binding also promotes receptor internalization and degradation, reducing active EGFRs on the cell surface. Cetuximab and panitumumab are examples of monoclonal antibodies used in cancer treatment. The effectiveness of these therapies often depends on specific EGFR gene mutations, highlighting the importance of molecular testing for personalized medicine.
References
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Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. G., Brannigan, B. A., … & Haber, D. A. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. New England Journal of Medicine, 350(21), 2129-2139.
Salomon, D. S., Brandt, R., Ciardiello, F., & Normanno, N. (2003). Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology/Hematology, 47(2), 77-114.
Baselga, J., & Arteaga, C. L. (2005). Critical update 2005: the epidermal growth factor receptor as a drug target in human cancer. Journal of Clinical Oncology, 23(11), 2452-2461.