The ERBB protein family consists of four related proteins that act as important communicators for cells throughout the body. These proteins function like cellular antennae, embedded within the cell membrane, receiving external signals. Upon receiving specific signals, they trigger a cascade of events inside the cell, orchestrating fundamental processes such as cell division and growth, which are important for healthy bodily functions.
The ERBB Family and Normal Cellular Function
The ERBB family includes four members: ERBB1, also known as Epidermal Growth Factor Receptor (EGFR) or HER1; ERBB2, also known as HER2; ERBB3, or HER3; and ERBB4, or HER4. These proteins are classified as receptor tyrosine kinases (RTKs), meaning they have an extracellular part that binds signals, a transmembrane part, and an intracellular part with enzyme activity. The intracellular part can add phosphate groups to tyrosine amino acids, a process called tyrosine phosphorylation, which is important for signal relay.
ERBB proteins bind to specific growth factors (ligands) outside the cell. This binding causes the ERBB receptors to pair up, forming either identical pairs (homodimers) or mixed pairs (heterodimers). This pairing activates their internal signaling machinery. For example, ERBB1 and ERBB4 are fully functional receptors that bind ligands and undergo autophosphorylation, while ERBB2 has no known direct ligand but prefers to partner with other ERBB receptors to activate signaling. ERBB3 also has impaired kinase activity and relies on its binding partners for activation through transphosphorylation.
Once activated, these paired receptors initiate a network of signals inside the cell. These signals are important for normal cellular processes, including cell division, growth, and differentiation, where cells specialize into different types. They also contribute to cell survival and migration, ensuring proper tissue development and maintenance. For instance, ERBB2 is required for normal embryonic development of neural crest-derived cranial sensory neurons and heart development, and ERBB3 is involved in the development of heart valves and neural crest differentiation. ERBB4 contributes to the development of the heart, central nervous system, and mammary gland, and its signaling is modulated by alternative splicing and proteolytic processing.
When ERBB Goes Wrong
When ERBB proteins become overactive or mutated, their regulation is disrupted, leading to uncontrolled cell growth and division. This dysregulation is a common feature in many cancers, transforming these proteins from normal cellular messengers into drivers of disease. Overexpression or mutations can lead to a continuous “on” signal, promoting unchecked proliferation.
ERBB1 (EGFR) is implicated in various cancers. Its overexpression or activating mutations are found in lung cancers (especially non-small cell lung cancer) and colorectal cancer. These alterations can lead to persistent activation of signaling pathways that drive tumor growth and resistance to therapies.
ERBB2 (HER2) is known for its role in breast cancer, where its amplification or overexpression occurs in about 20-30% of invasive cases, leading to aggressive disease. It is also overexpressed in gastric, ovarian, and lung cancers. The continuous signaling from overactive HER2 contributes to increased cell proliferation, tumor growth, and the potential for metastasis, which is the spread of cancer cells to other parts of the body. While cancer is the primary concern, other conditions, such as neurodegenerative diseases like multiple sclerosis and Alzheimer’s disease, can also be associated with insufficient or aberrant ERBB signaling.
Targeting ERBB for Treatment
Understanding ERBB protein dysregulation in cancer has led to targeted therapies designed to block their abnormal activity. These therapies offer a precise approach to treatment, often with fewer side effects than traditional chemotherapy. The two main types of ERBB-targeted drugs are monoclonal antibodies and tyrosine kinase inhibitors.
Monoclonal antibodies are proteins that bind to the extracellular part of ERBB receptors, preventing growth factor binding and receptor activation. For example, trastuzumab (Herceptin) targets HER2 in breast cancer, and cetuximab targets EGFR in colorectal and head and neck cancers. By blocking the initial signal, these antibodies can halt uncontrolled growth signals.
Tyrosine kinase inhibitors (TKIs) are molecules that can enter the cell and block the enzymatic activity of the ERBB receptor’s intracellular domain. These drugs, such as gefitinib and erlotinib for EGFR, and lapatinib for both EGFR and HER2, interfere with the signaling cascade inside the cell. They prevent the phosphorylation of tyrosine residues, shutting down the downstream pathways that promote cell proliferation and survival. The effectiveness of these targeted therapies often relies on personalized medicine, where tumors are tested for specific ERBB abnormalities, such as gene amplification or mutations, to guide treatment decisions. While these therapies have improved outcomes for many patients, challenges such as the development of drug resistance persist, driving ongoing research into new interventions.