The long-term objectives of this research program are to characterize the structure and function of protein tyrosine phosphatases (PTPs). The PTPs constitute a large family of signaling enzymes that together with protein tyrosine kinases (PTKs) modulate the cellular level of tyrosine phosphorylation. Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. Thus, a complete understanding of the physiological roles of protein tyrosine phosphorylation and how this process is deregulated in human diseases must necessarily encompass the characterization of PTPs. Such understanding may lead to the development of novel therapeutics that selectively target elements of signaling pathways for the treatment of human diseases. This competitive renewal focuses on SHP2 (Src homology 2 (SH2)-domain containing protein tyrosine phosphatase-2), which is the first bona fide oncoprotein identified in the PTP superfamily. SHP2 is ubiquitously expressed and positively regulates signaling from receptor tyrosine kinases through the activation of the Ras/ERK1/2 cascade. Consistent with its oncogenic role, germline autosomal dominant SHP2 mutations cause clinically similar LEOPARD syndrome (LS) and Noonan syndrome (NS), both of which are associated with increased risk of malignancy. In addition, somatic SHP2 mutations contribute to many forms of leukemia and solid tumors. However, although SHP2 mutations are associated with a number of developmental and neoplastic disorders, it remains unclear how SHP2 mutations alter cellular signaling to produce disease phenotypes. For example, NS or neoplasia-associated SHP2 mutants are constitutively active, resulting in gain-of-function effects. In contrast, mutations associated with LS reduce SHP2 phosphatase activity. These findings generated an enigma: how do SHP2 mutations with opposite effects elicit overlapping phenotypes? We hypothesize that pathogenic SHP2 mutations alter not only SHP2 phosphatase activity but also its molecular switching mechanism to drive disease outcomes and thus detailed understanding of the structure and function of SHP2 will reveal critical signaling events that underlie the diseases. The goals of this project ar to understand the molecular basis of disease-associated SHP2 mutations and to define the chain of molecular events coupling SHP2 dysfunction to the various LS abnormalities. A multidisciplinary approach, involving innovative combinations of X-ray crystallography, mass spectrometry, combinatorial chemistry, site-directed mutagenesis, enzyme kinetics, and cell biology will be employed to: 1) characterize the structural and biochemical properties of the LS mutants, and 2) define the signaling mechanisms mediated by the LS mutants. Successful completion of this project will create a solid framework for understanding how individual SHP2 mutations cause diseases and provide insight into novel points of therapeutic intervention for these diseases.

Public Health Relevance

This project is focused on the oncogenic protein tyrosine phosphatase SHP2. SHP2 mutations are known to cause a number of developmental disorders associated with increased risk of malignancy, multiple forms of leukemia, and solid tumors. This work will characterize the structural and biochemical properties of SHP2 mutants and define the mechanisms by which genetic mutations in SHP2 lead to various diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA069202-17A1
Application #
8434661
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Knowlton, John R
Project Start
1996-07-01
Project End
2017-11-30
Budget Start
2013-01-03
Budget End
2013-11-30
Support Year
17
Fiscal Year
2013
Total Cost
$301,815
Indirect Cost
$108,344
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Kobayashi, Michihiro; Bai, Yunpeng; Dong, Yuanshu et al. (2014) PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. Stem Cells 32:1956-67
Yu, Zhi-Hong; Zhang, Ruo-Yu; Walls, Chad D et al. (2014) Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry 53:4136-51
Liao, Jingling; Wu, Chun-Xiang; Burlak, Christopher et al. (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. Proc Natl Acad Sci U S A 111:4055-60
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Chen, Xiwu; Wang, Hongtao; Liao, Hong-Jun et al. (2014) Integrin-mediated type II TGF-? receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. J Clin Invest 124:3295-310
Dong, Yuanshu; Zhang, Lujuan; Bai, Yunpeng et al. (2014) Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis. J Biol Chem 289:3799-810
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Selner, Nicholas G; Luechapanichkul, Rinrada; Chen, Xianwen et al. (2014) Diverse levels of sequence selectivity and catalytic efficiency of protein-tyrosine phosphatases. Biochemistry 53:397-412
Nabinger, S C; Li, X J; Ramdas, B et al. (2013) The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo. Leukemia 27:398-408

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