The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells.
The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells.
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DOI：
10.18632/oncotarget.25101
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发表时间：
2018-05-04
期刊：
影响因子：
--
通讯作者：
Trapasso F
中科院分区：
文献类型：
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作者：
D'Agostino S;Lanzillotta D;Varano M;Botta C;Baldrini A;Bilotta A;Scalise S;Dattilo V;Amato R;Gaudio E;Paduano F;Palmieri C;Iuliano R;Perrotti N;Indiveri C;Fusco A;Gaspari M;Trapasso F
PTPRJ是一种受体蛋白酪氨酸磷酸酶，在人类癌症中强烈下调，通过负性调节几种参与增殖信号的蛋白来显示肿瘤抑制活性。在这里，我们通过基于蛋白质组学的方法，鉴定了一系列潜在的PTPRJ相互作用蛋白，其中我们重点研究了CD98hc，它是一种由SLC3A2编码的II型糖基化整膜蛋白，对应于包括LAT1在内的异源二聚体跨膜氨基酸转运体的重链。CD98hc在多种类型的癌症中广泛过表达，并通过干扰细胞的增殖、黏附和迁移而参与肿瘤的形成过程。我们首先验证了PTPRJ-CD98hc的相互作用，然后证明了PTPRJ的过表达显著降低了A549肺癌细胞中CD98hc的蛋白水平。此外，蛋白酶体抑制剂MG132处理PTPRJ转导细胞后，CD98hc水平与对照组相比没有下降，表明PTPRJ参与了CD98hc蛋白酶体降解的调节。此外，PTPRJ过表达结合CD98hc沉默持续抑制细胞增殖并触发肺癌细胞的凋亡。有趣的是，通过查询CAN EVERVE数据库，我们观察到PTPRJ和SLC3A2基因表达之间存在负相关。事实上，生存率短的非小细胞肺癌(NSCLC)分别表达最低水平的PTPRJ和最高水平的SLC3A2。因此，本文报道的结果有助于阐明癌细胞中的PTPRJ信号：此外，我们的发现还支持通过靶向PTPRJ的途径来开发一种新的抗癌治疗方法，而PTPRJ在高度恶性的人类肿瘤中通常下调。
PTPRJ, a receptor protein tyrosine phosphatase strongly downregulated in human cancer, displays tumor suppressor activity by negatively modulating several proteins involved in proliferating signals. Here, through a proteomic-based approach, we identified a list of potential PTPRJ-interacting proteins and among them we focused on CD98hc, a type II glycosylated integral membrane protein encoded by SLC3A2, corresponding to the heavy chain of a heterodimeric transmembrane amino-acid transporter, including LAT1. CD98hc is widely overexpressed in several types of cancers and contributes to the process of tumorigenesis by interfering with cell proliferation, adhesion, and migration. We first validated PTPRJ-CD98hc interaction, then demonstrated that PTPRJ overexpression dramatically reduces CD98hc protein levels in A549 lung cancer cells. In addition, following to the treatment of PTPRJ-transduced cells with MG132, a proteasome inhibitor, CD98hc levels did not decrease compared to controls, indicating that PTPRJ is involved in the regulation of CD98hc proteasomal degradation. Moreover, PTPRJ overexpression combined with CD98hc silencing consistently reduced cell proliferation and triggered apoptosis of lung cancer cells. Interestingly, by interrogating the can Evolve database, we observed an inverse correlation between PTPRJ and SLC3A2 gene expression. Indeed, the non-small cell lung cancers (NSCLCs) of patients showing a short survival rate express the lowest and the highest levels of PTPRJ and SLC3A2, respectively. Therefore, the results reported here contribute to shed lights on PTPRJ signaling in cancer cells: moreover, our findings also support the development of a novel anticancer therapeutic approach by targeting the pathway of PTPRJ that is usually downregulated in highly malignant human neoplasias.