The long term goal of this grant is to elucidate the mechanism through which mutations of receptor protein tyrosine phosphatase PTPRT lead to the development of colorectal cancers. This proposal tests the hypothesis that mutations of PTPRT impair critical tumor suppression functions leading to accelerated tumor growth and/or tumor progression through disrupting cell-cell adhesion and that `signal transducer and activator of transcription 3'(STAT3) plays critical roles in PTPRT regulated tumor suppressor signaling pathways.
The first aim of this proposal will investigate whether tumor specific mutations of PTPRT impair growth inhibitory functions in culture cells and in athymic nude mice xenograft models.
The second aim will determine whether STAT3 acts as the critical mediator of PTPRT regulated cell signaling pathway that is important in tumor development.
The third aim will determine whether tumor-derived mutations in the extracellular domain of PTPRT affect cell-cell adhesion. This proposal builds upon our successful exploitation of a cancer genomic approach that systematically explored the potential roles of protein tyrosine phosphatases in the development of colorectal cancer. Our initial study identified six tyrosine phosphatase genes that are mutated in 26% of colorectal cancers, providing compelling evidence that tyrosine phosphatases play critical roles in the development of colorectal cancers. PTPRT is the most frequently mutated tyrosine phosphatase gene among the six genes and over-expression of PTPRT inhibits growth of colorectal cancer cells. Recent work in this laboratory has now shown that the extracellular domain of PTPRT mediates homophilic binding, suggesting that PTPRT, like its close homologues, may also mediate cell-cell adhesion and thus play a critical role in tumor progression, given the fact that many metastatic cancers lose their cell adhesion properties. Using an innovative proteomic approach, we also identified STAT3, which is consistently activated in many cancers, as a PTPRT substrate. These observations emphasize the importance of determining whether STAT3 is a critical mediator of PTPRT tumor suppressor signaling and how tumor specific mutations affect tumor growth and cell-cell adhesion. Relevance: The proposed study will expand our understanding of new factors that cause colon cancer. This focus on new targets underlying colon cancer should facilitate design of novel approaches to treatment of cancer patients.
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|Zang, Wenwen; Hao, Yujun; Wang, Zhenghe et al. (2015) Novel thiourea-based sirtuin inhibitory warheads. Bioorg Med Chem Lett 25:3319-24|
|Zhao, S; Sedwick, D; Wang, Z (2015) Genetic alterations of protein tyrosine phosphatases in human cancers. Oncogene 34:3885-94|
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