SPACE PROVIDED. Many key processes are regulated by tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). Abnormal regulation of such pathways can lead to developmental defects and diseases such as cancer. Understanding cellular regulation requires defining the relevant PTKs and PTPs and their interactions. This in tum may lead to new, more selective drugs for human disease. The goal of our research is to understand the biological function, mechanism of action, and role in disease ofthe PTPs Shp2 and PTPIB. Shp2, encoded by PTPNU, is required for vertebrate development and is a positive (signal-enhancing) component in growth factor, cytokine and integrin signaling. Autosomal dominant PTPNU mutations cause half of Noonan syndrome (NS) and nearly all LEOPARD syndrome (LS). NS and LS are "neurocardiofacial cutaneous'(NCFC) syndromes, other examples of which include cardiofacial cutaneous syndrome (CFC), caused by BRAF or MEKl/2 mutations, and Costello Syndrome, caused by HRAS mutations. Most ofthe genes that cause NCFC syndromes are oncogenes, and most NCFC associated with cancer predisposition;Notably, somatic PTPNU mutations contribute to leukemias. Dxuing the initial years ofthis MERIT award, we characterized the properties of NS-associated Shp2 mutants and also found that, in contrast to the prevailing view, LS mutants are catalytically impaired, dominant negative alleles. We established thefirstmouse models for NS, delineated a key pathway by which Shp2 controls Ras activation, and identified the Ras exchange factor, SOSl as another major NS gene. In impublished, preliminary studies, we have identified a new, phosphatase activity-independent role for Shp2 in control of a p53-dependent cell death pathway, a pathwaytfiatmay help explain LS pathogenesis. PTPIB, in contrast, is typically a negative regulator of cell signaling. Surprisingly, however, we found that it is required for Neu-induced breast cancer. In the extension period, we will continue to use a combined genetic and ?- biochemical approach to understanding the detailed mechanism imderlying NCFC syndromes and the role of PTPIB in breast carcinogenesis. We will complete generation of mouse models for other NS genes and for CFC. We will define the Shp2 "phcsphotyrosyl proteome" and the new, activity-independent pathway controlling cell death. Finally, we will elucidate the detailied mechanism by which PITIB contributes to breast carcinogenesis, and assess whether thesefindingsextend to human HER2+ breast cancer. Oiu" results should be directly relevant to uiiderstanding the pathogenesis of human NCFC syndromes and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37CA049152-25
Application #
8447361
Study Section
Special Emphasis Panel (NSS)
Program Officer
Yassin, Rihab R,
Project Start
1988-12-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
25
Fiscal Year
2013
Total Cost
$311,658
Indirect Cost
$23,086
Name
University Health Network
Department
Type
DUNS #
208469486
City
Toronto
State
ON
Country
Canada
Zip Code
M5 2-M9
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Xu, Elaine; Forest, Marie-Pier; Schwab, Michael et al. (2014) Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPAR?. Hepatology 59:1803-15
Qiu, Wei; Wang, Xiaonan; Romanov, Vladimir et al. (2014) Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol 14:10
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Yang, Wentian; Wang, Jianguo; Moore, Douglas C et al. (2013) Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 499:491-5
Karisch, Robert; Neel, Benjamin G (2013) Methods to monitor classical protein-tyrosine phosphatase oxidation. FEBS J 280:459-75
Johnson, Dylan J; Pao, Lily I; Dhanji, Salim et al. (2013) Shp1 regulates T cell homeostasis by limiting IL-4 signals. J Exp Med 210:1419-31
Bassi, C; Ho, J; Srikumar, T et al. (2013) Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science 341:395-9
Abram, Clare L; Roberge, Gray L; Pao, Lily I et al. (2013) Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38:489-501
De Rocca Serra-Nedelec, Audrey; Edouard, Thomas; Treguer, Karine et al. (2012) Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature. Proc Natl Acad Sci U S A 109:4257-62

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