Rewriting Phosphorylation Codes: Toward Signal-State Editing with PhosTACs

Abstract

Protein phosphorylation is a dynamic post-translational modification (PTM) that regulates protein function, signaling, and cellular behavior. Accumulating evidence indicates that combinations of phosphosites function as “phosphorylation codes,” encoding distinct conformational and signaling states rather than acting independently. Dysregulation of these phosphorylation codes contributes to numerous diseases. Although therapies targeting protein kinases and phosphatases have achieved substantial clinical success, their indirect modulation of substrate phosphorylation leaves room for improved selectivity, reduced off-target effects, and greater resilience to therapeutic resistance. Here, we integrate current concepts of phosphorylation codes as a unifying framework for understanding phosphorylation-dependent regulation. Using tau and EGFR as representative models of pathological and signaling-state encoding, we further compare conventional kinase and phosphatase inhibitors with emerging induced-proximity technologies, including targeted protein degradation (TPD) of phosphorylation regulators and phosphorylation-targeting chimeras (PhosTACs), which recruit engineered or endogenous phosphatases to achieve targeted protein dephosphorylation (TPDephos). Together, these molecular strategies represent a conceptual progression from enzyme-centered intervention to event-driven editing of substrate phosphorylation states.