Protein tyrosine phosphatase receptor type R (PTPRR), a key member of the protein tyrosine phosphatase family, has been extensively studied for its complex regulatory functions within critical signaling pathways, notably the mitogen-activated protein kinase (MAPK) cascade. This review systematically examines the multifaceted roles of PTPRR in cancer, its underlying molecular mechanisms, and its potential as a therapeutic target. PTPRR expression is closely linked to the onset and progression of numerous cancers, highlighting its relevance as a research focus. However, its activity in tumors displays a context-dependent duality, and specific targeted drugs remain unavailable. We first outline the basic structure and function of PTPRR. As a protein tyrosine phosphatase, it negatively regulates cellular signaling through the dephosphorylation of specific substrates. Its distinct spatial architecture, particularly features of the catalytic domain and allosteric sites, provides a foundation for future targeted drug design. Under physiological conditions, PTPRR acts as an important modulator of major pathways such as MAPK and Wnt, thereby contributing to the regulation of cell growth, migration, and adhesion. A major emphasis of this review is to clarify the paradoxical behavior of PTPRR in cancer. In many malignancies, including colorectal and ovarian cancers, PTPRR acts as a classical tumor suppressor, and its silencing is associated with unfavorable prognosis. In contrast, its expression is markedly elevated in certain cancers such as adult T-cell leukemia/lymphoma. Even within a single cancer type, such as prostate cancer, PTPRR levels vary across disease stages. In bladder cancer, prognostic models based on anoikis and MAPK pathways respectively imply that PTPRR may confer protective or risk-promoting effects. These observations indicate that the function of PTPRR is highly contingent on cancer type, disease stage, and the specific tumor microenvironment. Mechanistically, PTPRR primarily constrains tumor initiation and progression by dephosphorylating key signaling molecules. The main known pathway involves negative feedback regulation of the MAPK/ERK (extracellular signal-regulated kinase) cascade: by dephosphorylating ERK1/2, PTPRR blocks downstream activation of oncogenic transcription factors, thereby suppressing tumor cell proliferation. Additionally, PTPRR directly targets β-catenin, a core component of the Wnt pathway, and counteracts its oncogenic activity via dephosphorylation. Together, these molecular interactions constitute the basis of its tumor-suppressive role. Despite progress in mechanistic understanding, the development of PTPRR-targeted therapies has been slow. No highly specific pharmacological agents are currently available. Existing strategies are largely indirect, such as using natural compounds like quercetin or epigenetic modifiers including DNA methylation inhibitors or histone deacetylase inhibitors to restore PTPRR expression. These approaches, however, often lack specificity, carry risks of off-target effects, and pose toxicity concerns. Therefore, future research must advance in several key directions. The primary objective is to develop small-molecule activators of PTPRR based on protein structure. Second, epigenetic editing technologies, including CRISPR/Cas9 systems, could be applied to selectively reverse promoter silencing of PTPRR, thus minimizing systemic side effects. Furthermore, exploring combination therapies of PTPRR modulators with other targeted agents, along with nanotechnology-based delivery systems, represents another promising strategy. In summary, PTPRR plays a complex and critical role in cancer biology. A deeper understanding of its context-dependent functions and mechanisms across tumor stages, coupled with efforts to translate this knowledge into specific targeted therapies, presents both a significant scientific challenge and a valuable opportunity to pioneer novel approaches in cancer treatment.
YANG et al. (Mon,) studied this question.