Zheng Chen, Liu Ting, Wang An Qi, Chen Xing An, Zhang Rong Zhe, Wang Xuan Chao, Lv Chao Yue, Pan Ru Lu, Wang Ou Chen, Lu Xin-Cheng
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
J Transl Med. 2025 May 12;23(1):534. doi: 10.1186/s12967-025-06496-1.
Protein Tyrosine Phosphatase Receptor Type Kappa (PTPRK) is a membrane-bound tyrosine phosphatase encoded by the frequently deleted region of chromosome 6q, which plays a crucial role in regulating cell signaling, adhesion, and immune response. Structurally, PTPRK comprises with an extracellular domain involved in cell-cell adhesion, a transmembrane region, and two intracellular catalytic domains responsible for its phosphatase activity. Notably, PTPRK undergoes proteolytic cleavage by Furin and ADAM10, resulting in the generation of an extracellular E-subunit and a P-subunit. Further processing by γ-secretase releases the intracellular PIC, which plays a pivotal role in regulating β-catenin signaling within the nucleus. PTPRK is widely recognized for its tumor-suppressive properties across various cancers, including colorectal, lung, ovarian, and melanoma. Despite its function as a tumor suppressor, the expression and activity of PTPRK exhibit considerable variability across different cancer types and stages. It exerts its effects by dephosphorylating key signaling molecules such as EGFR, STAT3, CD133 and β-catenin, thereby inhibiting cancer cell proliferation, survival, and metastasis. Beyond its role in cancer, PTPRK is also involved in immune regulation, particularly in the development of CD4 + T cells, and has been implicated in autoimmune diseases such as multiple sclerosis. In the nervous system, PTPRK is linked to neurite outgrowth and synaptic transmission, with genetic polymorphisms in PTPRK associated with an increased risk of neurodegenerative diseases like Alzheimer's disease. Given its extensive involvement in cancer biology, immune regulation, and neurodevelopment, PTPRK presents a promising therapeutic target. Strategies aimed at restoring its activity or targeting PTPRK might offer new approaches for current cancer therapies and overcome drug resistance. In this review, we elucidate the structural characteristics and functional roles of PTPRK in cellular signaling and disease pathogenesis. The variability of PTPRK suggests that the regulatory mechanisms governing its activity are intricate and worth further comprehensive investigation.
蛋白酪氨酸磷酸酶受体κ型（PTPRK）是一种由6号染色体长臂常见缺失区域编码的膜结合型酪氨酸磷酸酶，在调节细胞信号传导、黏附及免疫反应中发挥关键作用。在结构上，PTPRK由参与细胞间黏附的胞外结构域、跨膜区域以及负责其磷酸酶活性的两个胞内催化结构域组成。值得注意的是，PTPRK会被弗林蛋白酶和ADAM10进行蛋白水解切割，产生胞外E亚基和P亚基。γ-分泌酶的进一步加工会释放出胞内PIC，其在调节细胞核内的β-连环蛋白信号传导中起关键作用。PTPRK因其在包括结直肠癌、肺癌、卵巢癌和黑色素瘤在内的多种癌症中的肿瘤抑制特性而广为人知。尽管其作为肿瘤抑制因子发挥作用，但PTPRK的表达和活性在不同癌症类型和阶段表现出相当大的差异。它通过使关键信号分子如表皮生长因子受体（EGFR）、信号转导和转录激活因子3（STAT3）、CD133和β-连环蛋白去磷酸化来发挥作用，从而抑制癌细胞增殖、存活和转移。除了在癌症中的作用外，PTPRK还参与免疫调节，特别是在CD4 + T细胞的发育中，并且与自身免疫性疾病如多发性硬化症有关。在神经系统中，PTPRK与神经突生长和突触传递有关，PTPRK中的基因多态性与阿尔茨海默病等神经退行性疾病的风险增加有关。鉴于其在癌症生物学、免疫调节和神经发育中的广泛参与，PTPRK是一个有前景的治疗靶点。旨在恢复其活性或靶向PTPRK的策略可能为当前癌症治疗提供新方法并克服耐药性。在本综述中，我们阐明了PTPRK在细胞信号传导和疾病发病机制中的结构特征和功能作用。PTPRK的变异性表明，调控其活性的机制错综复杂，值得进一步全面研究。
