Protein Tyrosine Phosphatase Receptor Zeta 1 as a Potential Target in Cancer Therapy and Diagnosis

Abstract

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.

Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity

“…PTPRZ, also known as RPTPzeta, RPTPz, PTPζ, or RPTPβ, belongs to the subfamily of receptor-type PTPs [258,259]. PTPRZ expression is widespread during embryonic development but becomes restricted during adulthood [260]. Although the human PTPRZ1 gene encodes only the PTPRZ enzyme, its transcription produces 16 different mRNAs, including 14 alternatively spliced variants, 2 unspliced forms, and 3 known functionally identified splicing variants (PTPRZ-A, -B, and -S) [258][259][260].…”

“…PTPRZ expression is widespread during embryonic development but becomes restricted during adulthood [260]. Although the human PTPRZ1 gene encodes only the PTPRZ enzyme, its transcription produces 16 different mRNAs, including 14 alternatively spliced variants, 2 unspliced forms, and 3 known functionally identified splicing variants (PTPRZ-A, -B, and -S) [258][259][260]. Beyond alternative splicing, different PTPRZ forms can be derived from proteolytic processing [259,260].…”

“…Although the human PTPRZ1 gene encodes only the PTPRZ enzyme, its transcription produces 16 different mRNAs, including 14 alternatively spliced variants, 2 unspliced forms, and 3 known functionally identified splicing variants (PTPRZ-A, -B, and -S) [258][259][260]. Beyond alternative splicing, different PTPRZ forms can be derived from proteolytic processing [259,260]. Plasmin, TNF-α-converting enzyme, and MMP-9 cleave the extracellular domain of PTPRZ at multiple sites, releasing detectable extracellular PTPRZ fragments [259,260].…”

“…Beyond alternative splicing, different PTPRZ forms can be derived from proteolytic processing [259,260]. Plasmin, TNF-α-converting enzyme, and MMP-9 cleave the extracellular domain of PTPRZ at multiple sites, releasing detectable extracellular PTPRZ fragments [259,260]. Therefore, PTPRZ proteins are found in the cell membrane, cytoplasm, and nucleus, but we limit this chapter to transmembrane PTPRZ, which interacts with several cell adhesion molecules, such as integrins and nucleolin, likely responsible for PTPRZ translocation to the nucleus [259].…”

Cellular Components of the Tumor Environment in Gliomas—What Do We Know Today?

“…At the molecular level, the protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) has been shown to be an important link between oligodendrocytes and gliomas, as PTPRZ1 is involved in oligodendrocyte maturation and differentiation, and upregulation of its expression is known to be a major factor in the development of various cancers. Several signaling pathways such as the ß-catenin or the mTOR pathway have been shown to be among the downstream signaling pathways activated by PTPRZ1, and this activation occurs in glioma cells as well as in the stimulation of oligodendrocyte progenitor cell growth [132]. Despite this molecular link represented by the protein PTPRZ1, there is no clear evidence in TEM of a direct interaction between mature oligodendrocytes and gliomas.…”