| PZR (protein zero related, MPZL1) is a type I transmembrane glycoprotein of the immunoglobulin superfamily that localizes to the plasma membrane at cell–cell contacts and migration-associated structures and functions as a signaling scaffold linking extracellular cues to Src and SHP‑2–dependent pathways. The extracellular region carries Ig‑like domains with N‑glycosylation that support recognition by the lectin concanavalin A (ConA), while the short cytoplasmic tail of the full-length isoform contains a tandem pair of immunoreceptor tyrosine‑based inhibitory motifs with tyrosines that become phosphorylated by Src family kinases including c‑Src. PZR associates constitutively with c‑Src, and ConA binding to the glycoprotein triggers robust tyrosine phosphorylation of the ITIM tyrosines, enhanced c‑Src activation, and recruitment of the SH2 domain‑containing phosphatase SHP‑2, an interaction that is blocked by Src inhibitors such as PP1 and disrupted when the PZR cytoplasmic tail is truncated. These molecular events place PZR as a major receptor for ConA‑induced signaling, where the combination of Src activation and SHP‑2 binding to phosphorylated ITIMs modulates downstream cascades that influence cytoskeletal organization, cell morphology, and cell agglutination responses. Alternative splicing of the MPZL1 transcript generates isoforms PZRa and PZRb that lack ITIM motifs, and these variants retain extracellular and transmembrane regions but differ in their capacity to couple to SHP‑2 and to transduce Src‑dependent inhibitory or modulatory signals. PZR is enriched in cardiovascular, renal, and pancreatic tissues and concentrates at interendothelial junctions, where its adhesive and signaling properties have been linked to SHP‑2‑dependent regulation of endothelial barrier function and intercellular contact organization. Increased tyrosyl phosphorylation of PZR has been detected in genetic models with activating or dysregulated SHP‑2, including Noonan‑ and LEOPARD‑syndrome–associated PTPN11 variants, and this phosphorylation correlates with enhanced SHP‑2 membrane recruitment and altered growth and differentiation signaling in affected tissues. MPZL1 amplification and PZR overexpression are reported in several tumor types, where elevated PZR signaling associates with higher c‑Src activity, increased SHP‑2 engagement, and enhanced cell migration and invasive behavior, connecting this receptor-like adaptor to metastatic programs and to disease progression in hepatocellular carcinoma and other cancers. |
