HER2 ligands are molecules that interact with the Human Epidermal Growth Factor Receptor 2 (HER2) protein, influencing its activity. This interaction is important for understanding how cells grow and develop. Their involvement extends to both normal cellular functions and, when dysregulated, to the progression of certain diseases.
Understanding HER2 and Ligands
HER2 is a receptor protein located on the surface of cells. It is a receptor tyrosine kinase encoded by the ERBB2 gene and is one of four members of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. A ligand is a molecule that binds to a specific receptor, like a key fitting into a lock, triggering events inside the cell.
Unlike other HER family members, HER2 does not directly bind to a known ligand. Instead, HER2 activation primarily occurs through dimerization, where it pairs with another HER family receptor, such as HER1 (EGFR) or HER3, that has bound its own ligand. This pairing, or heterodimerization, activates the HER2 protein, initiating downstream signaling. HER2 can also homodimerize, forming a pair with another HER2 protein, especially when present at high concentrations.
The Normal Role of HER2 Ligands in Cell Growth
In healthy cells, HER2 and its ligands contribute to various physiological functions, including cell proliferation, survival, differentiation, and tissue development. When a ligand like neuregulin-1β binds to HER3, it facilitates the formation of a HER2-HER3 heterodimer.
This dimerization activates HER2’s intrinsic tyrosine kinase activity, leading to the phosphorylation of tyrosine residues within its intracellular domain. These phosphorylation events serve as docking sites for other signaling molecules, initiating intracellular pathways such as the MAPK and PI3K/Akt pathways. These pathways regulate gene transcription, which controls cell growth, migration, and survival, maintaining normal cellular processes.
HER2 Ligands and Cancer Development
The HER2 pathway can become dysregulated, playing a role in the development and progression of certain cancers. This often involves HER2 overexpression, where cells produce an abnormally high number of HER2 proteins on their surface. This overexpression is commonly due to an increase in copies of the ERBB2 gene, known as gene amplification. Some breast cancers can have up to 25-50 copies of the HER2 gene, leading to a 40-100-fold increase in HER2 protein, resulting in up to 2 million receptors on the tumor cell surface.
This abundance of HER2 receptors leads to excessive and uncontrolled signaling, even without high levels of activating ligands. The increased receptor density promotes constant cell division through homodimerization or enhanced heterodimerization. This uncontrolled cell division and survival contribute to tumor formation and progression. HER2 overexpression is a driver in approximately 15-30% of breast cancers and 10-30% of gastric/gastroesophageal cancers, and is also observed in other cancers like ovarian, endometrial, and lung cancers.
Targeting HER2 Ligands in Treatment
Understanding HER2 and its signaling pathways has led to the development of targeted therapies for HER2-positive cancers. These treatments aim to inhibit the abnormal HER2 signaling that drives cancer cell growth.
Monoclonal antibodies like Trastuzumab (Herceptin) are a common therapeutic approach. Trastuzumab binds to a specific part of the HER2 receptor, inhibiting downstream signaling and marking tumor cells for immune system attack. Another antibody, Pertuzumab (Perjeta), binds to a different site on HER2, preventing its dimerization with other HER family members. Combining Trastuzumab and Pertuzumab can provide a more complete blockade of HER2 signaling.
Tyrosine kinase inhibitors (TKIs) such as Lapatinib (Tykerb) and Neratinib are small molecules that block the intracellular signaling cascade by inhibiting the kinase activity of HER2 and other HER family receptors. These therapies work by disrupting abnormal growth signals, slowing or stopping the proliferation of HER2-positive cancer cells.