Disrupting the transmembrane domain?mediated oligomerization of protein tyrosine phosphatase receptor J inhibits EGFR-driven cancer cell phenotypes
Disrupting the transmembrane domain?mediated oligomerization of protein tyrosine phosphatase receptor J inhibits EGFR-driven cancer cell phenotypes
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DOI：
10.1074/jbc.ra119.010229
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发表时间：
2019-12-06
影响因子：
4.8
通讯作者：
Thevenin, Damien
中科院分区：
文献类型：
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作者：
Bloch, Elizabeth;Sikorski, Eden L.;Thevenin, Damien
受体蛋白酪氨酸磷酸酶（RPTPs）在哺乳动物信号转导中起着重要的调节作用。然而，调节其催化活性的结构基础尚未完全理解，并且RPTP通常不是治疗靶向的。这种知识差距部分是由于缺乏已知的天然配体或RPTP的选择性激动剂。与我们从结构中所知道的相反？受体酪氨酸激酶（RTK）的功能研究表明，RPTP活性被二聚体抑制，这可能会阻止RPTP接近其RTK底物。我们在这里报告的蛋白酪氨酸磷酸酶受体J（PTPRJ，也被称为DEP-1）的同源二聚体的特定跨膜（TM）残基的调节。我们发现，破坏这些相互作用会使细胞中全长PTPRJ的同源二聚体不稳定，降低已知PTPRJ底物表皮生长因子受体（EGFR）和其他下游信号效应物的磷酸化，拮抗EGFR驱动的细胞表型，并促进底物进入。我们使用突变研究在人类癌细胞中证明了这些观察结果，并鉴定了与PTPRJTM结构域结合的肽，其代表RPTP的变构激动剂的第一个例子。我们的研究结果为PTPRJ活性如何通过细胞中的TM相互作用进行调节提供了基本的结构和功能见解。我们的研究结果还为开发基于肽的药物提供了机会，这些药物可用作探测RPTP信号机制或管理RTK信号驱动的癌症的工具。
Receptor protein tyrosine phosphatases (RPTPs) play critical regulatory roles in mammalian signal transduction. However, the structural basis for the regulation of their catalytic activity is not fully understood, and RPTPs are generally not therapeutically targetable. This knowledge gap is partially due to the lack of known natural ligands or selective agonists of RPTPs. Contrary to what is known from structure?function studies of receptor tyrosine kinases (RTKs), RPTP activities have been reported to be suppressed by dimerization, which may prevent RPTPs from accessing their RTK substrates. We report here that homodimerization of protein tyrosine phosphatase receptor J (PTPRJ, also known as DEP-1) is regulated by specific transmembrane (TM) residues. We found that disrupting these interactions destabilizes homodimerization of full-length PTPRJ in cells, reduces the phosphorylation of the known PTPRJ substrate epidermal growth factor receptor (EGFR) and of other downstream signaling effectors, antagonizes EGFR-driven cell phenotypes, and promotes substrate access. We demonstrate these observations in human cancer cells using mutational studies and identified a peptide that binds to the PTPRJ TM domain and represents the first example of an allosteric agonist of RPTPs. The results of our study provide fundamental structural and functional insights into how PTPRJ activity is tuned by TM interactions in cells. Our findings also open up opportunities for developing peptide-based agents that could be used as tools to probe RPTPs' signaling mechanisms or to manage cancers driven by RTK signaling.