Many important biological processes are regulated by protein tyrosyl phosphorylation. Tyrosyl phosphorylation, in turn, is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatascs (PTPs). Abnormal regulation of these pathways can lead to developmental defects and diseases such as cancer. A complete understanding of cellular regulation by tyrosyl phosphorylation requires defining the PTKs and PTPs involved and determining how they interact. Such understanding may lead to the development of"""""""" new drugs that selectively target elements of these signaling pathways, agents that may be useful for the treatment of human disease. The goal of this research program is to further define the biological function and mechanism of action of the SH2 domain-containing PTP, Shp2. Shp2 is required lbr normal vertebrate development, and is an essential positive (i.e., signal-enhancing) component of multiple important signaling pathways, including those regulated by growth factors and extracellular matrix. Recent work indicates that autosomal dominant mutations of Shp2 are the cause of the human genetic disease Noonan syndrome (NS), and may play a role in the genesis of certain myeloid leukemias. In work during this funding period, we determined the phenotype of Shp2 protein-null embryos, generated the first dominant activating mutations of Shp2 and assessed their effects on early Xenopus development, showed that tyrosyl phosphorylation is critical for Shp2 function in some, but not all, growth factor signaling pathways, and found that Src is a key target fbr Shp2 regulation, most likely because Shp2 directly dephosphorylates the Csk regulator, Pag/Cbp. Nevertheless, several key questions about Shp2 function and mechanism of action remain, and are the topic of this continuation application. We will directly assess the biochemical properties of known NS mutations, determine whether somatic activating mutations of Shp2 occur in human lung and breast carcinomas, and analyze the effects of NS mutations in the mouse. We will clarify, the mechanism by which tyrosyl phosphorylation of Shp2 affects receptor tyrosine kinase signaling. The detailed mechanism by which Shp2 regulates Src activity via Pag/Cbp, and whether other Src family kinases are regulated similarly will be determined. Finally, we will determine how/whether defective Src activation contributes to the phenotype of Shp2-deficient cells, specifically, defective Ras/Erk activation and enhanced Rho activity. The results of our studies should yield new insights into the regulation of tyrosyl phosphorylation and the mechanism by which Shp2 mutations cause NS, and may reveal Shp2 to be a novel target for therapeutic intervention in human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37CA049152-20
Application #
7392354
Study Section
Pathology B Study Section (PTHB)
Program Officer
Yassin, Rihab R,
Project Start
1988-12-01
Project End
2009-01-31
Budget Start
2008-03-17
Budget End
2009-01-31
Support Year
20
Fiscal Year
2008
Total Cost
$321,845
Indirect Cost
Name
University Health Network
Department
Type
DUNS #
208469486
City
Toronto
State
ON
Country
Canada
Zip Code
M5 2-M9
Wang, Lijun; Iorio, Caterina; Yan, Kevin et al. (2018) A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages. FASEB J 32:875-887
Gu, S; Sayad, A; Chan, G et al. (2018) SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 32:203-213
Tsutsumi, Ryouhei; Harizanova, Jana; Stockert, Rabea et al. (2017) Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2. Nat Commun 8:466
Yao, Zhong; Darowski, Katelyn; St-Denis, Nicole et al. (2017) A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome. Mol Cell 65:347-360
Zhang, Xiaoling; Dong, Zhiwei; Zhang, Cheng et al. (2017) Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation. Cell Rep 18:2932-2942
Banh, Robert S; Iorio, Caterina; Marcotte, Richard et al. (2016) PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol 18:803-813
Gu, Shengqing; Chan, Wayne W; Mohi, Golam et al. (2016) Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1. Blood 127:1803-13
Dodd, Garron T; Decherf, Stephanie; Loh, Kim et al. (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160:88-104
Chiappini, Franck; Catalano, Karyn J; Lee, Jennifer et al. (2014) Ventromedial hypothalamus-specific Ptpn1 deletion exacerbates diet-induced obesity in female mice. J Clin Invest 124:3781-92
Gurzov, Esteban N; Tran, Melanie; Fernandez-Rojo, Manuel A et al. (2014) Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. Cell Metab 20:85-102

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