Promoting Receptor Protein Tyrosine Phosphatase Activity by Targeting Transmembrane Domain Interactions

通过靶向跨膜结构域相互作用促进受体蛋白酪氨酸磷酸酶活性

• 批准号: 10797721
• 负责人: Matthew J Lazzara
• 金额: $ 9.05万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797721
• 关键词: Affect; Binding; Biological; Biology; Cell Line; Cells; Complement; Computer Models; Data; Development; Dimerization; Disease Progression; Epidermal Growth Factor Receptor; Goals; Health; Heterodimerization; Homodimerization; Human; Knowledge; Mass Spectrum Analysis; Measurement; Mediating; Methods; Modeling; Molecular; Mus; Oncogenic; Outcome; PTPRJ gene; Peptides; Phenotype; Phosphorylation; Play; Predisposition; Protein Tyrosine Phosphatase; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Structure-Activity Relationship; Systems Biology; Testing; Therapeutically Targetable; Transmembrane Domain; Tyrosine Kinase Inhibitor; Variant; design; insight; mutant; novel therapeutic intervention; protein expression; receptor; trafficking; tumor xenograft

Below is the original Project Summary to fill this mandatory field Receptor protein tyrosine phosphatases (RPTPs) play critical signaling regulatory roles in development, health, and disease progression. Despite the clear importance of RPTPs in signal transduction, very little is known about the structure-function relationships that underpin the regulation of their activity. The reported ability of RPTP homodimerization to antagonize their catalytic activity, however, presents potential opportunities to develop strategies to promote RPTP activity against their oncogenic receptor tyrosine kinase (RTK) substrates. We recently showed, using PTPRJ/EGFR as a model RPTP/RTK pair, that: (i) homodimerization of PTPRJ (also known as DEP1) is regulated by transmembrane domain interactions, and (ii) disrupting these interactions can antagonize PTPRJ homodimerization, reduce substrate EGFR phosphorylation, and antagonize EGFR-driven cell phenotypes. Here, we propose to build upon these new insights along three thematically interconnected, but non- overlapping, specific aims, with the ultimate goals of: (1) demonstrating that RPTP TM domain interactions are essential in regulating their activity and substrate access, and (2) developing a new therapeutic approach to promote RPTP activity against their oncogenic RTK substrates. In our first aim, we will determine the molecular determinants regulating the heterodimerization of PTPRJ with EGFR. These studies will be complemented by extending them to understand how PTPRJ TM domain mutants affect receptor trafficking and ultimate cell outcomes. In the second aim, we will design and select peptides capable of binding to PTPRJ TM domains and test their ability to disrupt PTPRJ homodimerization, promote PTPRJ activity against EGFR and other substrate RTKs, and selectively target human tumor xenografts in mice. In the third aim, we will identify other candidate RTK substrates whose regulation by PTPRJ depends upon TM domain-mediated heterodimerization, and determine how different cellular contexts predict the cell signaling and phenotype outcome of interfering with PTPRJ dimerization through TM domains. To do so, we will implement a systems biology approach based on data-driven computational modeling of phenotypic measurements and global mass spectrometry measurements of protein phosphorylation and expression in a panel of cell lines. This aim is motivated by an understanding that all RPTPs have multiple substrates and that variations in expression of those substrates among cells may lead to different outcomes when PTPRJ dimerization is disrupted. Ultimately, the studies proposed here stand to advance both our basic biological understanding of RPTP biology, which is critically needed, and to lead to new methods to target signaling through oncogenic RTKs that may be less susceptible to common mechanisms of acquired resistance to RTK inhibitors.

以下是填写此强制性字段的原始项目摘要 受体蛋白酪氨酸磷酸酶（RPTPS）在发育中起关键的信号调节作用， 健康和疾病进展。尽管RPTP在信号转导中显然很重要，但很少 了解基于其活性调节的结构 - 功能关系。报告 然而 制定策略以促进RPTP活动针对其致癌受体酪氨酸激酶的策略 （RTK）基材。我们最近使用PTPRJ/EGFR作为型号RPTP/RTK对表明：（i） PTPRJ（也称为DEP1）的同构化受跨膜结构域的相互作用和 （ii）破坏这些相互作用会拮抗PTPRJ同二聚化，减少底物EGFR 磷酸化，并拮抗EGFR驱动的细胞表型。 在这里，我们建议沿着三个主题相互联系但非 - 重叠，具体目标，其最终目标是：（1）证明RPTP TM域相互作用是 调节其活动和底物的访问至关重要，以及（2）开发一种新的治疗方法 针对其致癌RTK底物促进RPTP活性。 在我们的第一个目标中，我们将确定调节PTPRJ异构化的分子决定因素 egfr。这些研究将通过扩展以了解PTPRJ TM结构域突变体如何进行补充 影响受体运输和最终细胞结局。在第二个目标中，我们将设计并选择肽 能够与PTPRJ TM域结合并测试其破坏PTPRJ同二聚化的能力，促进 针对EGFR和其他底物RTK的PTPRJ活性，并选择性地靶向人类肿瘤异种移植物 老鼠。在第三个目标中，我们将确定其他候选RTK基质的ptprj依赖 在TM结构域介导的异二聚化时，并确定不同的细胞环境如何预测细胞 通过TM域干扰PTPRJ二聚化的信号传导和表型结果。为此，我们 将基于表型的数据驱动计算建模来实现系统生物学方法 A蛋白磷酸化和表达的测量和全球质谱测量 细胞系的面板。理解所有RPTP都有多个底物，并且该目标的动机是 当PTPRJ时，这些底物表达的表达变化可能会导致不同的结果 二聚化被破坏。 最终，这里提出的研究旨在提高我们对RPTP的基本生物学理解 生物学，这是非常需要的，并导致通过致癌RTK靶向信号的新方法 可能不太容易受到对RTK抑制剂的耐药性的常见机制。

项目成果

Disrupting PTPRJ transmembrane-mediated oligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD.

• DOI: 10.3389/fonc.2022.1017947
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Schwarz, Marie;Rizzo, Sophie;Paz, Walter Espinoza;Kresinsky, Anne;Thevenin, Damien;Mueller, Joerg P.
• 通讯作者: Mueller, Joerg P.

Identifying Transmembrane Interactions in Receptor Protein Tyrosine Phosphatase Homodimerization and Heterodimerization.

识别受体蛋白酪氨酸磷酸酶同二聚和异二聚中的跨膜相互作用。

• DOI: 10.1007/978-1-0716-3569-8_13
• 发表时间: 2024
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Rizzo,Sophie;Thévenin,Damien
• 通讯作者: Thévenin,Damien