Role of PTPRT in colon cancer progression and metastasis

PTPRT 在结肠癌进展和转移中的作用

基本信息

批准号：
10527892
负责人：
Zhenghe Wang
金额：
$ 44.1万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-24 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10527892
关键词：
3-nitrotyrosine Alleles Antibodies Belief Binding Binding Proteins Bioinformatics C-terminal Cancer Etiology Cancer Science Carbon Carcinogens Cell Line Cells Cessation of life Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer Colorectal Neoplasms Data Development Disease Enzymes Extravasation Follow-Up Studies Foundations Frameshift Mutation Genes Genetic Goals HCT116 Cells Head and neck structure Human In Vitro Knock-in Knock-in Mouse Knock-out Knockout Mice Knowledge Laboratories Lung Malignant Neoplasms Membrane Mus Mutant Strains Mice Mutate Mutation Nature Neoplasm Metastasis Nitrogen Nonsense Mutation Oncogenic Organoids Ovarian Oxygen PH Domain Patients Penetrance Phenols Phosphoric Monoester Hydrolases Phosphotransferases Phosphotyrosine Play Positioning Attribute Protein Tyrosine Phosphatase Proteins Reader Role Seminal Signal Pathway Signal Transduction Specificity Specimen Stomach Tertiary Protein Structure Testing Tumor Suppressor Proteins Tumor-Derived Tyrosine United States cancer cell cancer type cellular transduction colon cancer metastasis colon cancer progression colon tumorigenesis colorectal cancer progression epigenetic silencing in vivo innovation melanoma metastatic colorectal migration mutant nitration paxillin protein function receptor src Homology Region 2 Domain success tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

Protein tyrosine phosphatase receptor T (PTPRT) is frequently mutated in human cancers, including colorectal cancer. PTPRT has two tyrosine phosphatase domains. While the membrane-proximal domain is an active protein tyrosine phosphatase, it has been thought that the C-terminal domain is a pseudo-phosphatase lacking enzymatic activity. Our preliminary data demonstrated that the pseudo-phosphatase domain of PTPRT is an active enzyme, termed denitrase, that removes nitro-groups (NO₂ at the 3-carbon position of the phenol ring of tyrosine) from the Y333 residue in ERK and Y404 residue paxillin. We demonstrated that nitro-Y333 (nY333) Erk increases its kinase activity, whereas nitro-Y404 (nY404) paxillin is likely to transduce cell signal through a “reader” (nY binding protein). Further, we generated denitrase-inactivating mutant knockin mice and showed that the mutant mice are susceptible to carcinogen-induced colon tumor development. Recently, several recent bioinformatics studies demonstrated that PTPRT mutations, including those in the denitrase domain, are enriched in metastatic colorectal cancers, suggesting that inactivation of PTPRT denitrase promotes tumor metastasis. Thus, we hypothesize that the PTPRT-regulated ERK and paxillin nitration signaling pathways play a critical role in colorectal progression and metastasis. Three aims are proposed to test this central hypothesis by determining the role of: (1) PTPRT denitrase-regulated paxillin nitration signaling in colorectal cancer progression and invasion; and (2) PTPRT denitrase-regulated Erk nitration signaling in colorectal cancer progression and metastasis. Protein tyrosine nitration is currently believed to be a byproduct of reactive oxygen/nitrogen species and not regulated by enzymes. Success in our proposed studies will establish protein tyrosine nitration as a critical player in colorectal tumor progression and metastasis.

蛋白酪氨酸磷酸酶受体 T (PTPRT) 在人类癌症中经常发生突变，包括结直肠癌 PTPRT 有两个酪氨酸磷酸酶结构域，而近膜结构域是一个活性结构域。蛋白酪氨酸磷酸酶，曾被认为C端结构域是缺乏的假磷酸酶我们的初步数据表明 PTPRT 的假磷酸酶结构域是一个酶活性。活性酶，称为脱硝酶，可去除硝基（苯酚环 3-碳位置上的 NO2）酪氨酸）来自 ERK 中的 Y333 残基和 Y404 残基桩蛋白我们证明了硝基-Y333 (nY333) Erk。增加其激酶活性，而硝基-Y404 (nY404) 桩蛋白可能通过此外，我们还生成了脱硝酶失活的突变型敲入小鼠，并证明了这一点。突变小鼠易受致癌物诱发的结肠肿瘤的影响。生物信息学研究表明，PTPRT 突变（包括脱硝酶结构域中的突变）与在转移性结直肠癌中富集，表明 PTPRT 脱硝酶失活可促进肿瘤发生因此，我们发现 PTPRT 调节的 ERK 和桩蛋白硝化信号通路发挥着作用。提出了三个目标来检验这一中心假设。通过确定以下作用：(1) PTPRT 脱硝酶调节的桩蛋白硝化信号在结直肠癌中的作用 (2)结直肠癌中 PTPRT 脱硝酶调节的 Erk 硝化信号传导目前认为蛋白质酪氨酸硝化是反应的副产物。我们提议的研究的成功将建立蛋白质。酪氨酸硝化在结直肠肿瘤进展和转移中发挥着关键作用。