The broad, long-term objectives of this project are to characterize the structure, regulation and physiological function of members of the protein tyrosine phosphatase (PTP) family of enzymes. In the area of tyrosine phosphorylation-dependent signal transduction, drug discovery efforts to date have emphasized the protein tyrosine kinases (PTKs). However, protein tyrosine phosphorylation is reversible and, therefore, there is the potential to manipulate signal transduction pathways at the level of both PTKs and PTPs. The composition of the PTP family has been determined and significant progress has been made in elucidating the physiological functions of these enzymes. Tumor-derived mutations have been identified in multiple PTP genes and examples of PTPs as either the products of oncogenes or tumor suppressors have been established. Although the PTPs have been garnering attention as potential therapeutic targets, they remain largely an untapped resource. In the previous funding period, a broad array of tools and technologies has been developed to permit a systematic analysis of PTP function from the perspective of the family as a whole. This competitive renewal has been focused on a functional analysis of specific PTPs in models of breast cancer. The hypothesis to be tested is that PTPs function as specific regulators of tyrosine phosphorylation-dependent signaling pathways and thus manipulation of PTP function in cell and animal models will reveal new insights into the critical signaling events that underlie the disease. The overall goal is to define functional links between particular PTPs and specific signaling pathways in breast cancer, with a view to establishing how disruption of such functions affects the etiology of the disease and to reveal novel therapeutic targets from among the PTPs themselves or from the signaling pathways they regulate.
The Specific Aims of this research program are: 1: To characterize the role of PTP1B in regulating signaling by HER2, 2: To characterize the function of PTPs in the control of HER2-induced cell migration and invasion, focusing on PTPRG, PTPRR and PTPN23, 3: To identify and characterize PTPs that modify HER2 signaling in 3D culture, focusing initially on PTPRO and PTPRJ/DEP-1, 4: To determine how loss of expression of PTPs contributes to tumorigenesis in vivo.
Each cell is surrounded by a plasma membrane that represents a barrier to the outside world. However, a cell must be able to respond to changes in its external environment. This laboratory studies a process termed signal transduction, which is the mechanism by which cells register environmental stimuli and respond by changing their growth, differentiation, survival, movement or metabolism. The reversible addition and removal of phosphate to proteins, which is termed protein phosphorylation, is a crucial aspect of the mechanism of signal transduction. The activities of the enzymes that mediate the addition (kinases) and removal (phosphatases) of phosphate groups are coordinated in signal transduction pathways to mediate the cellular response to environmental stimuli and the function of these enzymes is frequently disrupted in human diseases, including cancer. This laboratory focuses on the family of signal transducing protein phosphatases known as Protein Tyrosine Phosphatases (PTPs) and their role in human disease. The ability to modulate signal transduction pathways selectively holds enormous therapeutic potential. The first drugs directed against protein tyrosine kinases (PTKs) have now entered the market and represent breakthroughs in cancer therapy. These include small molecules such as Gleevec (STI-571), an inhibitor of the p210 BCR-ABL oncoprotein PTK for the treatment of chronic myelogenous leukemia, and the EGF receptor kinase inhibitors Iressa (Gefitinib) and Tarceva (Erlotinib) for treatment of non-small cell lung cancer. Breast cancer remains a major unmet medical need and the development of novel therapeutic strategies is of paramount importance. The HER2 gene, which encodes a protein tyrosine kinase, is amplified and/or overexpressed in several cancers, in particular in ~25% of breast cancer, where it associated with poor prognosis. Herceptin (Trastuzumab), a humanized HER2-directed antibody, has been developed as an example of a rational cancer therapy. Nevertheless, the success rate is limited and there are examples of patients developing resistance to these therapies. Overall, these approaches remain in their infancy and the development of novel strategies to interrogate such protein phosphorylation-dependent signaling pathways will have a profound impact on drug development in cancer. I am proposing a systematic analysis of the role of the family of protein tyrosine phosphatases in breast cancer. These enzymes coordinate with kinases such as HER2 in the regulation of signal transduction and cell function, but remain largely an untapped resource in drug discovery efforts. The overall goal is to define functional links between particular members of the PTP family and specific signaling pathways in breast cancer, with a view to establishing how disruption of such functions underlies the etiology of the disease and to reveal novel therapeutic targets from among the PTPs themselves or from the signaling pathways they regulate.
|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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