The ERBB signaling pathway is a fundamental communication system within cells, playing a significant role in various biological activities. It transmits signals from outside the cell to its interior, influencing cell behavior and maintaining overall cellular health and function.
The Basics of ERBB Signaling
ERBB stands for Epidermal Growth Factor Receptor family, a group of proteins that act like antennas on the cell surface. This family includes four members: EGFR (also known as ERBB1 or HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). These receptors are single-chain glycoproteins with an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyrosine kinase domain. Ligands, which are signaling molecules, bind to the extracellular domain of ERBB receptors, initiating a cascade of events.
The binding of a ligand, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGFα) to EGFR, causes the receptor to change shape and form a dimer, either with another EGFR or with another ERBB family member. For instance, ERBB2 does not have a known direct ligand but readily forms heterodimers with other ERBB receptors, acting as a signal amplifier. ERBB3, despite having ligands like neuregulin (NRG1 or NRG2), has a kinase domain that lacks catalytic activity and relies on other ERBB members, often ERBB2, for phosphorylation and signal transduction. This dimerization and subsequent activation of the intracellular tyrosine kinase domain lead to the phosphorylation of specific tyrosine residues, creating docking sites for other signaling proteins and initiating a chain reaction within the cell.
How ERBB Signaling Works Normally
Under normal conditions, the ERBB signaling pathway precisely regulates a variety of cellular processes. It plays a role in cell growth, cell division, cell differentiation, and cell survival.
This pathway is also linked to broader physiological processes, including embryonic development, tissue repair, and maintaining the healthy state of various organs, such as the skin, lungs, and mammary glands. For example, ERBB2 and ERBB4 are important for heart development, and ERBB3 is involved in the peripheral nervous system.
When ERBB Signaling Goes Awry
When the ERBB signaling pathway becomes dysregulated, it can lead to various diseases, with a prominent role in cancer development. Overactivity or mutations within ERBB receptors are frequently observed in several types of cancer, including breast, lung, and colorectal cancer. For instance, overexpression or amplification of ERBB2 (HER2) is found in 15% to 30% of breast cancers, often associated with more aggressive disease and poorer patient outcomes. In colorectal cancer, ERBB2 alterations, including overexpression and amplification, are detected in about 5% of metastatic cases.
These dysregulations can cause uncontrolled cell growth and proliferation, as continuous pathway activation bypasses normal regulatory mechanisms. Mutations in ERBB genes can lead to persistent activation of downstream signaling pathways, even without external ligands, driving tumor growth and increasing resistance to programmed cell death. For example, activating mutations in EGFR are linked to non-small cell lung cancer, and specific mutations in ERBB2 can contribute to colorectal cancer progression. Abnormal signaling can also promote metastasis, where cancer cells spread to other parts of the body.
ERBB-Targeted Therapies
The comprehensive understanding of ERBB pathway dysregulation has paved the way for the development of specific medical treatments known as targeted therapies. These therapies are designed to interfere with the abnormal signals produced by dysfunctional ERBB receptors, offering a more precise approach compared to traditional chemotherapy. One type of ERBB-targeted drug involves monoclonal antibodies, which are large proteins that bind to the extracellular domain of the receptors, blocking ligand binding and preventing receptor dimerization. Trastuzumab and pertuzumab are examples of such antibodies used in ERBB2-positive breast cancer, with pertuzumab offering a more comprehensive signal blockade when combined with trastuzumab.
Another class of targeted therapies includes small molecule inhibitors (SMIs), also known as tyrosine kinase inhibitors (TKIs), which are capable of entering the cell and directly blocking the internal signaling activity of the ERBB receptors. Lapatinib, for instance, is a dual EGFR/HER2 kinase inhibitor used in breast cancer, while tucatinib selectively targets HER2. These small molecules work by interfering with the phosphorylation process within the receptor’s intracellular domain, thereby interrupting the downstream signaling cascades that drive cell proliferation and survival in cancer cells. This approach represents a form of precision medicine, where treatments are tailored to the specific molecular characteristics of a patient’s disease, leading to improved outcomes in certain cancer types.