Role of PTPRT in colon cancer 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 癌PTPRT具有两个酪氨酸磷酸酶结构域。而膜近端结构域是一个活性的 蛋白质酪氨酸磷酸酶，已经认为C-末端结构域是缺乏蛋白质酪氨酸磷酸酶的假磷酸酶。 酶活性我们的初步数据表明，PTPRT的假磷酸酶结构域是一个 一种活性酶，称为脱氮酶，能除去酚环3-碳位上的硝基（NO）。 酪氨酸）的ERK中的Y333残基和Y 404残基桩蛋白。我们证明了硝基-Y333（nY 333）Erk 增加其激酶活性，而硝基-Y 404（nY 404）桩蛋白可能通过抑制细胞信号传导， “阅读器”（nY结合蛋白）。此外，我们产生了去活化腺苷酸酶的突变敲入小鼠，并表明， 突变小鼠对致癌物诱导的结肠肿瘤发展敏感。最近，几个 生物信息学研究表明，PTPRT突变，包括那些在蛋白酶结构域， 在转移性结直肠癌中富集，表明PTPRT转移酶的失活促进肿瘤生长。 转移因此，我们假设PTPRT调节的ERK和桩蛋白硝化信号通路在细胞内起作用。 在结直肠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设 通过确定以下因素的作用：（1）在结直肠癌中，PTPRT酶调节的桩蛋白硝化信号 进展和侵袭;和（2）PTPRT激酶调节的大肠癌中的Erk硝化信号传导 进展和转移。目前认为蛋白质酪氨酸硝化是反应性硝化的副产物。 氧/氮物质，不受酶的调节。在我们的研究中取得成功将建立蛋白质 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.