The broad, long-term objectives of the project are to characterize the structure, regulation and function of the protein tyrosine phosphatase (PTP) 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 and metabolism. Furthermore, disruption of the delicate balance between the action of PTPs and PTKs has been implicated in the etiology of human diseases, including cancer, diabetes and inflammation. Therefore, characterization of the PTPs is a prerequisite to gaining a complete understanding of the physiological consequences of tyrosine phosphorylation under normal and diseased conditions. This competitive renewal focuses on a new tier of control of tyrosine-phosphorylation dependent signal transduction, the regulation of PTP function by reversible oxidation.
The Specific Aims of the proposal are: 1) To develop new strategies to assay reversible oxidation of PTPs and to determine the stoichiometry of oxidation in response to physiological stimuli. 2) To investigate the interplay between PTP oxidation and the control of pTyr-dependent signaling. 3) To investigate mechanisms underlying the specificity of stimulus-induced PTP oxidation. 4) To investigate the potential function of the second PTP domain in Receptor PTPs as an oxidation sensor. New assays will be developed to measure the reversible oxidation of PTPs in response to physiological stimuli. Furthermore, such oxidation will be harnessed as a means of """"""""tagging"""""""" the specific PTPs that are integral to the regulation of signal transduction pathways initiated by those stimuli. By combining the use of RNA interference with application of substrate trapping mutant forms of the PTPs, the signaling function of these enzymes will be defined. It is anticipated that the insights that are generated may identify novel targets for therapeutic intervention in human disease and may suggest new therapeutic strategies for PTP inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055989-11
Application #
7236669
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Program Officer
Anderson, Richard A
Project Start
1997-05-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
11
Fiscal Year
2007
Total Cost
$369,649
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; Bonham, Christopher A; Rus, Ioana A et al. (2018) Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nat Commun 9:283
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
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
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
Chaudhary, Fauzia; Lucito, Robert; Tonks, Nicholas K (2015) Missing-in-Metastasis regulates cell motility and invasion via PTP?-mediated changes in SRC activity. Biochem J 465:89-101
Pulido, Rafael; Baker, Suzanne J; Barata, Joao T et al. (2014) A unified nomenclature and amino acid numbering for human PTEN. Sci Signal 7:pe15

Showing the most recent 10 out of 51 publications