ITGB4 (integrin subunit beta 4) is a critical structural component of hemidesmosomes in epithelial cells, functioning as part of the integrin α6/β4 heterodimer that serves as a laminin receptor 1. This integrin mediates cell-matrix adhesion and plays essential roles in regulating keratinocyte polarity and motility [UniProt annotation]. ITGB4 also functions as a signaling receptor, binding growth factors including neuregulin-1, IGF1, and IGF2 to facilitate their respective signaling pathways [UniProt annotation]. Mechanistically, ITGB4 maintains epithelial barrier function through hemidesmosomal assembly 1. Loss of ITGB4 in airway epithelial cells disrupts this barrier and triggers the SHP2/JNK/c-Jun/FGF2 signaling pathway, leading to epithelial-mesenchymal trophic unit (EMTU) activation 1. ITGB4 also regulates endothelial cell senescence through the mTORC2/AKT/p53 pathway via direct interaction with FLRT2 2. Clinically, biallelic ITGB4 mutations cause junctional epidermolysis bullosa with severe skin fragility 3. Beyond monogenic diseases, ITGB4 expression is elevated in multiple cancer contexts, including head and neck squamous cell carcinoma where it predicts EGFR therapy response and correlates with invasion and tumor budding 4. ITGB4 upregulation also contributes to acquired resistance in lung cancer through AKT-mTOR bypass signaling 5, and marks a clonogenic progenitor population in lung organoids 6.