Beyond the membrane: rethinking EGFR signaling in physiology and cancer

The epidermal growth factor receptor (EGFR) functions as a central signaling hub that integrates biochemical and mechanical cues essential for tissue development, homeostasis, and disease. Emerging evidence highlights how EGFR activity is finely regulated through its spatial organization at the plasma membrane, intracellular trafficking pathways, and interactions with organelles via specialized membrane contact sites. In addition to its well-established ligand-dependent activation, EGFR also mediates ligand- and kinase-independent functions, adding further complexity to its roles in physiology and pathology, particularly in cancer. This review explores how ligand diversity, cellular context, and mechanical stimuli converge to shape EGFR signaling, emphasizing the integration of ligand-dependent and -independent mechanisms in determining cellular outcomes. We also discuss how these emerging functions influence cancer cell metabolism and survival. A deeper understanding of these intricate signaling networks may inform the development of novel therapeutic strategies to modulate EGFR activity in cancer.