Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a type V transmembrane tyrosine phosphatase that is highly expressed during embryonic development, while its expression during adulthood is limited. PTPRZ1 is highly detected in the central nervous system, affecting oligodendrocytes’ survival and maturation. In gliomas, PTPRZ1 expression is significantly upregulated and is being studied as a potential cancer driver and as a target for therapy. PTPRZ1 expression is also increased in other cancer types, but there are no data on the potential functional significance of this finding. On the other hand, low PTPRZ1 expression seems to be related to a worse prognosis in some cancer types, suggesting that in some cases, it may act as a tumor-suppressor gene. These discrepancies may be due to our limited understanding of PTPRZ1 signaling and tumor microenvironments. In this review, we present evidence on the role of PTPRZ1 in angiogenesis and cancer and discuss the phenomenal differences among the different types of cancer, depending on the regulation of its tyrosine phosphatase activity or ligand binding. Clarifying the involved signaling pathways will lead to its efficient exploitation as a novel therapeutic target or as a biomarker, and the development of proper therapeutic approaches.

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