The broad, long-term objectives of the project are to characterize the structure, regulation and function of the protein tyrosine phosphatase (FTP) family of enzymes. It is now apparent that the coordinated and competing actions of both protein tyrosine kinases {PTKs) and PTPs are integrated in vivo to control such fundamental processes as growth and proliferation, differentiation, survival, motility andmetabolism. Furthermore, disruption of the delicate balance between the action of PTPs and PTKs has been implicatedin the etiology of human diseases. Therefore, characterization of the PTPs is a prerequisite to gaininga complete understanding of the physiological consequences of tyrosine phosphorylaticn under normal diseased conditions. This research program is focused primarily on two nontransmembrane PTPs, PTP1B and TCPTP, which have been shown to be critical regulators of growth factor and hormone-induced signal transduction pathways in vivo, with links to major human diseases including cancer and diabetes.The four Specific Aims are;1) To conduct a structure:function analysis of PTP1B that will define mechanismsof substrate recognition and regulation of enzymatic activity, 2} To characterize the PTP 1Bpromoter and elucidate mechanims by which expression of the PTP is alteredin human diseases, 3) To characterize the regulation and function of TCPTP and 4) To develop proteomics-based strategies for profiling theexpression of members of the PTP family. Both PTP1B and TCPTP are regulated by reversible oxidation in vivo, which induces inhibitory conformational changes of the PTP active site. Strategies have been developedto test whether trapping the oxidized, inactive conformation can be pursued to exploit the PTPs astherapeutic targets. Furthermore, proteomics-based strategies are being developed for PTP identification in biological samples, to define novel therapeutic targets for human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA053840-18
Application #
7390872
Study Section
Special Emphasis Panel (NSS)
Program Officer
Yassin, Rihab R,
Project Start
1991-08-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
18
Fiscal Year
2008
Total Cost
$668,025
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Krishnan, Navasona; Felice, Christy; Rivera, Keith et al. (2018) DPM-1001 decreased copper levels and ameliorated deficits in a mouse model of Wilson's disease. Genes Dev 32:944-952
Krishnan, Navasona; Konidaris, Konstantis F; Gasser, Gilles et al. (2018) A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models. J Biol Chem 293:1517-1525
Zhang, Siwei; Fan, Gaofeng; Hao, Yuan et al. (2017) Suppression of protein tyrosine phosphatase N23 predisposes to breast tumorigenesis via activation of FYN kinase. Genes Dev 31:1939-1957
Gurung, Prajwal; Fan, Gaofeng; Lukens, John R et al. (2017) Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1?-Mediated Inflammatory Disease. Immunity 46:635-648
Fan, Gaofeng; Zhang, Siwei; Gao, Yan et al. (2016) HGF-independent regulation of MET and GAB1 by nonreceptor tyrosine kinase FER potentiates metastasis in ovarian cancer. Genes Dev 30:1542-57
Fan, Gaofeng; Aleem, Saadat; Yang, Ming et al. (2015) Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase. J Biol Chem 290:15934-47
Ramesh, Mathangi; Krishnan, Navasona; Muthuswamy, Senthil K et al. (2015) A novel phosphatidic acid-protein-tyrosine phosphatase D2 axis is essential for ERBB2 signaling in mammary epithelial cells. J Biol Chem 290:9646-59
Krishnan, Navasona; Krishnan, Keerthi; Connors, Christopher R et al. (2015) PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J Clin Invest 125:3163-77
Krishnan, Navasona; Tonks, Nicholas K (2015) Anxious moments for the protein tyrosine phosphatase PTP1B. Trends Neurosci 38:462-5
Fan, Gaofeng; Wrzeszczynski, Kazimierz O; Fu, Cexiong et al. (2015) A quantitative proteomics-based signature of platinum sensitivity in ovarian cancer cell lines. Biochem J 465:433-42

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