Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece.
Laboratory of Molecular Respiratory Carcinogenesis, Faculty of Medicine, Department of Physiology, University of Patras, Patras, Greece.
Int J Cancer. 2023 Sep 1;153(5):1051-1066. doi: 10.1002/ijc.34564. Epub 2023 Jun 1.
Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A (VEGFA ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1 and Ptprz1 mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1 lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1 LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1 compared with Ptprz1 mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (β ) integrin is decreased in Ptprz1 LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1 mice. A selective PTPRZ1 TP inhibitor, VEGFA and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN.
蛋白酪氨酸磷酸酯酶受体 ζ1（PTPRZ1）是一种跨膜酪氨酸磷酸酶（TP），在血管内皮细胞中表达，对于血管内皮生长因子 A（VEGFA）和多效蛋白（PTN）刺激细胞迁移是必需的。它在各种肿瘤类型中也存在过表达或低表达。在本研究中，我们使用基因工程 Ptprz1 和 Ptprz1 小鼠来研究 PTPRZ1 参与血管生成的机制方面，并研究其在肺腺癌（LUAD）生长中的作用。Ptprz1 肺微血管内皮细胞（LMVEC）与 Ptprz1 LMVEC 相比具有增加的血管生成特征，这与 Ptprz1 相比 Ptprz1 小鼠中的肺血管生成增加和化学诱导的 LUAD 生长增强一致。在从用尿烷处理的小鼠肺部分离的 LUAD 细胞中，PTPRZ1 TP 抑制也增强了增殖和迁移。Ptprz1 LMVEC 中β3（β）整合素的表达减少，与增强的血管内皮生长因子受体 2（VEGFR2）、c-Met 酪氨酸激酶（TK）和 Akt 激酶活性有关。然而，只有 c-Met 和 Akt 似乎负责 Ptprz1 小鼠中体外增强的内皮细胞激活以及体内 LUAD 生长和血管生成。一种选择性的 PTPRZ1 TP 抑制剂、VEGFA 和 PTN 也以 PTPRZ1 依赖的方式在血管内皮细胞中激活 c-Met 和 Akt，并且它们的刺激作用被 c-Met TK 抑制剂（TKI）克唑替尼废除。总之，我们的数据表明，低 PTPRZ1 表达与 LUAD 预后较差以及对 c-Met TKIs 的反应相关，并首次揭示了 PTPRZ1 在介导 VEGFA 和 PTN 激活 c-Met 中的作用。
