The broad, long-term objectives of this research program are to characterize the structure and function of protein tyrosine phosphatases (PTPs). The PTPs constitute a large family of signaling enzymes that together with protein tyrosine kinases (PTKs) modulate the cellular level of tyrosine phosphorylation. Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. Thus, a complete understanding of the physiological roles of protein tyrosine phosphorylation and how this process is deregulated in human diseases must necessarily encompass the characterization of PTPs. Such understanding may lead to the development of novel therapeutics that selectively target elements of signaling pathways for the treatment of human diseases. This competitive renewal focuses on a novel class of PTPs, the PRL (phosphatase of regenerating liver) phosphatases, which are implicated in cell growth and migration. In particular, PRL3 is overexpressed in a variety of tumors and high levels of PRL3 expression are associated with tumor metastasis. Consistent with an oncogenic role for PRL3, ectopic expression of PRL3 enhances cell growth, causes cell transformation, and promotes tumor metastasis. Thus, PRL3 may represent an attractive target for anticancer therapy. Unfortunately, how PRL3 functions at the molecular and cellular level is not understood. In addition, the identities of PRL3 substrate(s) and the signaling pathways regulated by PRL3 are not known. The goals of this project are to understand the structure and function of PRL3, and to determine the mechanism(s) by which PRL3 controls cell growth and migration. A multidisciplinary approach, involving a combination of mutagenesis, biochemical and cellular assays, hydrogen/deuterium exchange, X-ray crystallography, and mass spectrometry-based proteomics will be used to: 1) Assess the functional significance of PRL3 trimer formation, 2) Determine the structural basis of PRL3-phospholipids interaction, 3) Elucidate the cellular pathway(s) regulated by PRL3, and 4) Identify PRL3 substrates with the substrate-trapping approaches. The emerging results from the proposed studies will increase our understanding of the molecular basis of PRL3 function, and lead to the identification of PRL3 substrates as well as the cellular pathways regulated by PRL3. Obtaining this knowledge is vital for understanding PRL3-mediated tumor metastasis, and for the development of novel anticancer therapies targeted to PRL3.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069202-15
Application #
7741259
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Knowlton, John R
Project Start
1996-07-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
15
Fiscal Year
2010
Total Cost
$301,177
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ruddraraju, Kasi Viswanatharaju; Zhang, Zhong-Yin (2017) Covalent inhibition of protein tyrosine phosphatases. Mol Biosyst 13:1257-1279
Kobayashi, M; Bai, Y; Chen, S et al. (2017) Phosphatase PRL2 promotes oncogenic NOTCH1-Induced T-cell leukemia. Leukemia 31:751-754
Kobayashi, M; Chen, S; Bai, Y et al. (2017) Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia. Leukemia 31:1453-1457
Yamashita, Naoya; Joshi, Rajshri; Zhang, Sheng et al. (2017) Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors. Dev Cell 42:626-639.e5
Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng et al. (2017) Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors. Stem Cells 35:1053-1064
Sacchetti, Cristiano; Bai, Yunpeng; Stanford, Stephanie M et al. (2017) PTP4A1 promotes TGF? signaling and fibrosis in systemic sclerosis. Nat Commun 8:1060
Bai, Yunpeng; Zhou, Hong-Ming; Zhang, Lujuan et al. (2016) Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis. Sci Rep 6:34211
Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan et al. (2016) Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest 126:2077-92
Maeshima, Keisuke; Stanford, Stephanie M; Hammaker, Deepa et al. (2016) Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 1:
Hamerman, Jessica A; Pottle, Jessica; Ni, Minjian et al. (2016) Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases. Immunol Rev 269:212-27

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