ERBB3 is a receptor tyrosine kinase that functions as a cell surface receptor for neuregulins, particularly neuregulin-1 (NRG1) 1. Upon ligand binding, ERBB3 undergoes phosphorylation and associates with the p85 subunit of phosphatidylinositol 3-kinase, activating downstream survival and proliferation pathways 1. Despite its kinase domain being functionally defective, ERBB3 activates prominent signaling through PI3K/AKT pathways and interacts with multiple downstream effectors including GRB, SHC, and SRC 2. ERBB3 plays critical roles in cell differentiation and development, particularly in enteric neuron specification and cardiac homeostasis 34. Disease relevance is substantial and multisystem. Loss-of-function ERBB3 mutations cause complex developmental syndromes including Hirschsprung disease, contracture syndromes, and gastrointestinal dysmotility 53. In cancer, ERBB3 is frequently amplified or mutated across multiple tumor types including colorectal, pancreatic, breast, and lung cancers, contributing to treatment resistance 672. Additionally, ERBB3 dysregulation associates with pulmonary hypertension through endothelial dysfunction 8 and type 1 diabetes susceptibility 9. Reduced circulating ERBB3 correlates with heart failure risk and cardiovascular mortality independent of diabetes status 4. These findings establish ERBB3 as a therapeutic target across multiple pathologies.