Role of PTPRT in colon cancer progression and metastasis

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.