The Epidermal Growth Factor (EGF) signaling pathway allows cells to respond to external cues. EGF is a small protein, or growth factor, released by one cell to signal others. This pathway regulates fundamental biological processes, including cell growth, movement, differentiation, and tissue repair. Coordinating these signals is necessary for the normal development and maintenance of healthy tissues.
The Epidermal Growth Factor Receptor
The initial target for the EGF signal is the Epidermal Growth Factor Receptor (EGFR), a protein anchored in the cell membrane. Also known as ErbB1 or HER1, this transmembrane receptor has three main parts: an extracellular domain for binding the growth factor, a transmembrane segment, and an intracellular domain with tyrosine kinase activity. When EGF binds to the external domain, it triggers a shape change, causing two individual EGFR molecules to form a dimer.
This dimerization activates the receptor’s internal tyrosine kinase domains, which phosphorylate each other on specific tyrosine residues in the cytoplasmic tail. This process, called autophosphorylation, converts the external EGF message into an internal cellular signal. The phosphorylated tyrosine residues serve as docking sites for various adaptor proteins and enzymes. The EGFR ensures the cell’s response is directly tied to the presence of the external growth factor.
Targets Controlling Cell Proliferation
Cell proliferation is a primary outcome of EGF signaling, mediated by the RAS-MAPK cascade. The activated EGFR recruits an adaptor protein complex, including GRB2 and SOS, to the cell membrane. SOS acts as a guanine nucleotide exchange factor, activating the small G-protein RAS by causing it to bind GTP. This activation essentially flips RAS’s molecular switch to the “on” position.
Activated RAS recruits and activates the protein kinase RAF at the membrane. RAF then phosphorylates and activates MEK (Mitogen-activated protein kinase kinase). MEK subsequently phosphorylates and activates ERK (Extracellular signal-regulated kinase).
Activated ERK travels from the cytoplasm into the cell nucleus, targeting transcription factors. ERK phosphorylates proteins like ELK-1, which partners with other factors to activate genes promoting cell cycle progression, such as FOS and JUN. These genes code for proteins forming the AP-1 transcription factor complex, which drives the cell into active growth and division. Because this pathway promotes cell division, mutations that leave components like RAS or RAF constantly active are frequently found in human cancers.
Targets Controlling Cell Survival and Metabolism
The PI3K/AKT/mTOR cascade is a parallel pathway activated by the EGFR that controls cell survival. Phosphoinositide 3-kinase (PI3K) is recruited to the EGFR docking sites and becomes active at the cell membrane. PI3K converts the membrane lipid PIP2 into the signaling lipid PIP3.
PIP3 acts as a second messenger, recruiting the protein kinase AKT (Protein Kinase B) to the membrane for activation by kinases like PDK1. Once activated, AKT travels throughout the cell, phosphorylating targets that promote survival by blocking apoptosis, or programmed cell death. For example, AKT inhibits pro-death proteins like BAD, preventing premature cell death.
AKT also activates the Mammalian Target of Rapamycin (mTOR), which regulates cell metabolism and protein synthesis. mTOR activation upregulates protein production and nutrient uptake, allowing the cell to increase its size and biomass. This function focuses on the cell growing larger and remaining viable before division.
Targets Controlling Cell Movement and Structure
The EGF pathway targets proteins enabling the cell to change shape and move, a process called motility. This function is controlled through the activation of Phospholipase C-gamma (PLC gamma), which is recruited to the activated EGFR and phosphorylated. Active PLC gamma cleaves a membrane lipid to generate two second messengers: Inositol trisphosphate (IP3) and Diacylglycerol (DAG).
IP3 diffuses into the cytoplasm and binds to endoplasmic reticulum receptors, causing the release of stored calcium ions. DAG remains at the cell membrane and, along with the calcium, activates Protein Kinase C (PKC). These molecules influence the activity of Rho GTPases, which regulate the cell’s cytoskeleton.
The signals influence proteins like Rac1, which drives the reorganization of actin filaments. This leads to the formation of sheet-like protrusions that push the cell forward. This reorganization is essential for processes like wound healing, where cells migrate to close a gap, and plays a role in the invasive movement of cancer cells.