The broad, long-term objectives of this project are to characterize the structure, modes of regulation and physiological function of members of the protein tyrosine phosphatase (PTP) family of enzymes. The reversible phosphorylation of tyrosyl residues in proteins, catalyzed by the coordinated actions of protein tyrosine kinases (PTKs) and phosphatases (PTPs), is of critical importance to the regulation of signaling events that underlie such fundamental processes as growth and proliferation, migration differentiation, metabolism and cytoskeletal function. Disturbance of this delicate balance between the PTKS and PTPs has been shown to be a cause of human diseases including cancer, diabetes and inflammation. Clearly a characterization of the PTPs will be a prerequisite to achieving a complete understanding of the physiological consequences of tyrosine phosphorylation and how this process is abrogated in the pathogenesis of human disease. In this competitive renewal, the research program is focused primarily on two non-transmembrane PTPs that have been shown to exert selective effects on signal transduction in vivo - PTP1B, which has been implicated in the regulation of insulin receptor signaling, and TCPTP, which regulates EGF-induced signal transduction. Detailed structure-function analyses will be applied to examine at the molecular level the mechanism of substrate recognition, catalysis and regulation of these enzymes. In addition, substrate trapping mutant forms of these enzymes, a powerful technology developed as part of this research program, will be utilized to identify their physiological substrates, thus yielding critical insights into function. It has been noted that expression of PTP 18 is induced at the transcriptional level in several disease contexts. Therefore, a characterization of its promoter is proposed. Finally, in this post-genomic era of biological research, the proposal is made to develop strategies for profiling PTPs present in defined cell types and subcellular compartments, with the long-term goal of establishing novel links between members of the PTP family and human disease states. In view of these objectives, the Specific Aims are: 1) To conduct a structure-function analysis of PTP1B that will define mechanisms of substrate recognition and regulation of enzymatic activity, 2) To characterize the PTP1B promoter and elucidate mechanisms by which expression of the PTP is altered in human disease, 3) To characterize the regulation and function of TCPTP and 4) To develop proteomics-based strategies for profiling the expression of members of the PTP family.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37CA053840-11
Application #
6335726
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
1991-08-01
Project End
2006-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
11
Fiscal Year
2001
Total Cost
$608,814
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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