Many important biological processes are regulated by protein tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein- tyrosine phosphatases (PTPs). Abnormal regulation of these pathways can lead to developmental abnormalities 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 is needed to develop new agents 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 define the biological function and mechanism of action of an SH2 domain-containing PTP, SHP-2. SHP-2 is required for normal development of frogs and mice, and acts within a number of important signaling pathways, including PTK pathways regulated by growth factors and extracellular matrix. However, its detailed functions remain to be elucidated. First, they will further define the role of SHP2 in early vertebrate development, using Xenopus and mouse models. The Xenopus studies will employ dominant negative SHP2 mutants, along with novel """"""""activated"""""""" SHP2 mutants. In the mouse studies, they will characterize the embryonic lethal phenotype of SHP2-null, Exon-2 deleted mice. Using genetic analysis, we will then determine whether and how SHP2 acts as a limiting component in RTK signaling by asking how/whether decreasing SHP2 dosage affects mice with defective EGFRs (waved-2), and mice which overexpress TGF-a in their mammary epithelium (WAP-TGFa). Using reverse genetics and cell lines derived from SHP2 mutant mice, they will delineate SHP2's role in integrin signaling and RTK signaling. The mechanism by which the SHPS1/SHP2 complex regulates fibronectin-induced signaling will be determined and the direct targets of SHP2 in EGF receptor and FGF receptor signaling will be defined. Finally, by monitoring the biological activity of chimeras between SHP2 and its relative, SHP1, in Xenopus mesoderm induction, they will determine how/why these two highly similar PTPs have such distinct biological roles. The results of these studies should yield new insights into how tyrosyl phosphorylation is controlled and, in particular, how PTPs contribute to its regulation. In addition, their studies may reveal SHP2 to be a good target for therapeutic intervention in human tumors with elevated EGFR activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049152-15
Application #
6614432
Study Section
Pathology B Study Section (PTHB)
Program Officer
Spalholz, Barbara A
Project Start
1988-12-01
Project End
2003-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
15
Fiscal Year
2003
Total Cost
$537,902
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Peled, Michael; Tocheva, Anna S; Sandigursky, Sabina et al. (2018) Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor. Proc Natl Acad Sci U S A 115:E468-E477
Xu, Yang; Taylor, Paul; Andrade, Joshua et al. (2018) Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma. Cancer Res 78:6539-6548
Fedele, Carmine; Ran, Hao; Diskin, Brian et al. (2018) SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models. Cancer Discov 8:1237-1249
Gu, S; Sayad, A; Chan, G et al. (2018) SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 32:203-213
Cimmino, Luisa; Neel, Benjamin G; Aifantis, Iannis (2018) Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol 28:698-708
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
Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao et al. (2017) Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 170:1079-1095.e20
Ran, Hao; Tsutsumi, Ryouhei; Araki, Toshiyuki et al. (2016) Sticking It to Cancer with Molecular Glue for SHP2. Cancer Cell 30:194-196
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

Showing the most recent 10 out of 85 publications