The ERBB family of receptor tyrosine kinases (RTKs) plays a crucial role in cell growth, differentiation, and survival. It consists of four members: ERBB1 (EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). Epidermal growth factor (EGF) and other related growth factors bind to the extracellular domains of ERBB receptors, primarily EGFR (ERBB1). ERBB2 has no known direct ligand and relies on heterodimerization with other ERBB receptors. ERBB3 can bind heregulin but has impaired kinase activity. Dimerization: Upon ligand binding, ERBB receptors undergo conformational changes that promote their dimerization (homodimerization or heterodimerization). Heterodimerization, particularly with ERBB2, often leads to enhanced and prolonged signaling. ERBB2 is a preferred dimerization partner due to its constitutively active kinase domain and lack of direct ligand binding. It acts as a co-receptor, enhancing the signaling of other ERBB receptors. The phosphorylated tyrosine residues serve as docking sites for various signaling proteins containing Src homology 2 (SH2) domains. These proteins include adapter molecules and enzymes. Recruitment of these proteins activates several downstream signaling pathways, including activation of Ras, followed by Raf, MEK, and ERK, which leads to gene expression involved in cell proliferation and survival. Activation of PI3K, followed by Akt and mTOR, promotes cell growth, survival, and protein synthesis. STAT proteins are recruited to the receptors, phosphorylated, and then translocate to the nucleus to regulate gene transcription.
PLCγ Pathway: Phospholipase C-gamma activation leads to the production of diacylglycerol and inositol triphosphate, affecting calcium signaling and protein kinase C activation. Dysregulation of ERBB signaling, such as overexpression, amplification, or mutations of ERBB receptors (particularly EGFR and HER2), is frequently observed in various cancers. This leads to uncontrolled cell proliferation, survival, and metastasis. The importance of ERBB signaling in cancer has led to the development of targeted therapies, such as tyrosine kinase inhibitors (TKIs) that block the kinase activity of ERBB receptors, and monoclonal antibodies that target the extracellular domains of these receptors. Overall, ERBB signaling is a complex and finely tuned network essential for normal cellular processes. Its dysregulation contributes significantly to disease, making it a critical area of research and therapeutic intervention, especially in oncology.