The Epidermal Growth Factor Receptor (EGFR) is a protein on the outer surface of many cells. It acts as a receiver for external signals that direct cells to grow, divide, and survive. Like an antenna, it translates messages for the cell’s internal machinery.
The Architectural Blueprint of EGFR
The EGFR protein is a complex structure with distinct regions, each having a specific role. It is a single polypeptide chain, typically around 170-180 kilodaltons in mass, composed of approximately 1186 amino acids. This protein spans the cell membrane, creating segments both outside and inside the cell.
The extracellular domain extends outside the cell, acting as the cell’s “docking station” or receiver. This large region is where specific growth factor molecules, known as ligands, bind. It consists of four subdomains (I, II, III, and IV, or L1/CR1/L2/CR2) that collectively form the binding site for these external signals.
The transmembrane domain anchors the receptor within the cell’s outer boundary. This segment is an alpha-helical structure that passes directly through the cell’s lipid membrane. Its primary role is to connect the extracellular portion to the intracellular machinery.
The portion located inside the cell is the intracellular domain. This domain contains two functional regions. The tyrosine kinase domain possesses enzymatic activity that adds phosphate groups to other proteins, initiating a signaling cascade.
Following the kinase domain is the C-terminal tail. This tail contains multiple tyrosine residues that can be phosphorylated once the kinase domain is active. These phosphorylated tyrosines then become docking sites for other proteins, allowing the signal to be relayed within the cell.
Activation Mechanism and Structural Changes
Activation of EGFR begins when a specific growth factor, such as epidermal growth factor (EGF), arrives in the extracellular environment. This growth factor binds specifically to the extracellular domain of the EGFR protein, causing a change in the receptor’s shape.
This shape alteration then enables two individual EGFR molecules to pair up on the cell surface, a process called dimerization. While some evidence suggests EGFR may exist as an inactive dimer before ligand binding, ligand binding is understood to induce the conformational changes required for full activation and proper orientation of these paired receptors.
Once two EGFR molecules have paired, their intracellular tyrosine kinase domains move into close proximity. This allows them to activate each other in a process known as autophosphorylation. Each kinase domain adds phosphate groups to specific tyrosine residues on the C-terminal tail of its partner.
This addition of phosphate groups switches the EGFR receptor on. These newly phosphorylated tyrosine sites serve as binding points for other signaling proteins within the cell. This binding initiates a cascade of events, transmitting growth and division signals, influencing cellular behavior.
Consequences of a Flawed Structure
The EGFR structure is important for its proper function, and any deviation can have major consequences for cell behavior. Changes in the genetic code, known as mutations, can alter the protein’s structure, leading to a malfunctioning receptor. These mutations can occur in various parts of the EGFR gene, affecting different domains of the protein.
A common outcome of such structural alterations is that the EGFR becomes constantly activated, even in the absence of a growth factor ligand. This continuous activation sends uncontrolled signals for cell growth and division. For instance, in non-small cell lung cancer (NSCLC), specific activating mutations often involve small deletions in exon 19 or a point mutation called L858R in exon 21, both located within the intracellular kinase domain.
These mutations stabilize the kinase domain in an active conformation. Another example is glioblastoma, an aggressive brain cancer, where common EGFR alterations include in-frame deletions that result in the EGFRvIII variant, which lacks portions of the extracellular domain, leading to ligand-independent activation. Other mutations, such as A289V or A289D, also occur in the extracellular domain of EGFR in glioblastoma.
This signal bypasses the normal regulatory mechanisms that control cell growth. The uncontrolled cell division driven by these flawed EGFR structures is a characteristic of cancer. Understanding these specific structural defects is therefore important for developing effective treatments.
Targeting EGFR Structure in Cancer Therapy
Understanding of EGFR’s structure and its activation mechanism has paved the way for developing targeted cancer therapies. These therapies are designed to interfere with the receptor’s function. Two main classes of drugs are employed to achieve this.
One class consists of small molecule inhibitors, commonly known as Tyrosine Kinase Inhibitors (TKIs). These drugs are small enough to enter the cell and target the intracellular kinase domain of EGFR. They work by occupying the ATP-binding site, preventing ATP binding.
By blocking this site, TKIs like gefitinib, erlotinib, or afatinib prevent the kinase domain from phosphorylating other proteins. Some TKIs, such as afatinib and osimertinib, form an irreversible covalent bond with a specific cysteine residue (Cys797) in the ATP-binding site, ensuring a sustained blockade of kinase activity.
The second class of targeted drugs comprises monoclonal antibodies. These are larger molecules that cannot enter the cell, so they exert their effect on the extracellular domain of EGFR. Monoclonal antibodies, such as cetuximab and panitumumab, are engineered to bind to this domain.
Their binding blocks growth factors from attaching to EGFR. This interference prevents conformational changes and dimerization of EGFR molecules on the cell surface. By stopping the initial steps of activation, these antibodies prevent the “on” switch, inhibiting the signaling pathway.