PZR: Advances in research from cellular signaling Hub to emerging therapeutic targets.

Protein Zero Related (PZR) is a type I transmembrane glycoprotein encoded by the MPZL1 gene and a member of the immunoglobulin superfamily (IgSF). Despite sharing 46 % sequence homology in its extracellular domain with myelin P0 protein (MPZ), PZR exhibits distinct functional specialization. It undergoes alternative splicing to generate three isoforms (PZR, PZRa, PZRb) with tissue-specific expression patterns, predominantly enriched in cardiovascular, renal, and pancreatic tissues, and localized to cell-cell contact sites and migration-associated domains, consistent with its roles in adhesion and motility. Functionally, PZR serves as a multifunctional signaling hub, acting as both a receptor for concanavalin A (ConA) and a regulator of SH2 domain-containing protein tyrosine phosphatase-2 (SHP-2) and Src family kinases. ConA binding triggers c-Src activation, leading to PZR autophosphorylation and subsequent recruitment of SHP-2. Its intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) further mediate interactions with Src kinases and SHP-2, driving oncogenesis, immunomodulation, and antiviral responses. Post-translational modifications, including phosphorylation and glycosylation, enhance its protein-binding capacity, enabling broad influence over physiological and pathological processes, particularly in tumor microenvironment signaling and cellular fate regulation. Initially implicated in Noonan syndrome and schizophrenia, recent studies highlight PZR as a critical regulator of cancer cell adhesion and migration, with dysregulation accelerating disease progression. This review systematically analyzes the structural and functional properties of PZR, explores its disease-associated molecular mechanisms, and integrates emerging evidence to propose PZR as a promising therapeutic target. By delineating its signaling networks and pathophysiological roles, we provide a framework for advancing diagnostic and therapeutic strategies targeting PZR-related disorders.