Role of PTPRT in colon cancer progression and metastasis

蛋白酪氨酸磷酸酶受体T(PTPRT)在包括结直肠癌在内的人类肿瘤中经常发生突变 癌症。PTPRT有两个酪氨酸磷酸酶结构域。而膜近端结构域是一种活跃的 蛋白酪氨酸磷酸酶，一直认为C-末端结构域是一种缺乏的假性磷酸酶 酶活性。我们的初步数据表明，PTPRT的伪磷酸酶结构域是一种 一种活性酶，称为脱硝酶，能去除硝基(在苯酚环的3-碳位置上没有₂ 酪氨酸)来自ERK中的Y333残基和Y404残基的帕西林。我们证明了硝基-Y333(NY333)Erk 增加其激酶活性，而硝基-Y404(NY404)巴西林可能通过一种 “Reader”(NY结合蛋白)。此外，我们还获得了脱氮酶失活突变敲击小鼠，并表明 突变的小鼠对致癌物诱导的结肠癌的发展很敏感。最近，几个最近的 生物信息学研究表明，PTPRT突变，包括脱硝酶结构域中的突变，是 在转移性结直肠癌中丰富，表明PTPRT脱硝酶失活促进肿瘤 转移。因此，我们假设PTPRT调节的ERK和帕西林硝化信号通路发挥作用 在结直肠癌的进展和转移中起关键作用。提出了三个目标来检验这一中心假说 通过确定：(1)PTPRT脱硝酶调节的帕西林硝化信号在结直肠癌中的作用 (2)PTPRT脱硝酶调节的ERK硝化信号在结直肠癌中的作用 进展和转移。蛋白质酪氨酸硝化目前被认为是反应性的副产品。 氧/氮物种，不受酶的调节。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起关键作用。

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.