Scaffold-mediated phosphatase regulation in EGFR family signaling

The epidermal growth factor receptor (EGFR) family serves as an archetypal model of receptor tyrosine kinase signaling and plays essential roles in development, tissue homeostasis, and cancer. Although receptor phosphorylation has been extensively studied, the mechanisms governing dephosphorylation remain comparatively obscured. A limited repertoire of protein tyrosine phosphatases (PTPs) directly regulates EGFR family receptors, yet their signaling specificity cannot be explained by intrinsic catalytic activity alone. Accumulating evidence indicates that PTP function is governed by higher-order mechanisms that control subcellular localization, receptor accessibility, and integration into dynamic signaling networks. In this Review, we summarize the PTPs that directly regulate the EGFR family and examine how scaffold proteins, membrane organization, intracellular trafficking, and organelle-specific platforms coordinate receptor dephosphorylation. We propose a functional taxonomy comprising five categories: assembly, localization, membrane-organizing, organelle, and regulatory scaffolds. This framework provides a basis for understanding signaling specificity and suggests therapeutic strategies targeting the spatiotemporal organization of phosphatase function.