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.
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.
|Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan et al. (2016) Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest 126:2077-92|
|Dutta, Noton K; He, Rongjun; Pinn, Michael L et al. (2016) Mycobacterial Protein Tyrosine Phosphatases A and B Inhibitors Augment the Bactericidal Activity of the Standard Anti-tuberculosis Regimen. ACS Infect Dis 2:231-239|
|Bai, Yunpeng; Zhou, Hong-Ming; Zhang, Lujuan et al. (2016) Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis. Sci Rep 6:34211|
|Li, Yu; Xia, Guiquan; Guo, Qi et al. (2016) Design, synthesis and evaluation of novel (19)F magnetic resonance sensitive protein tyrosine phosphatase inhibitors. Medchemcomm 7:1672-1680|
|Bai, Yunpeng; Yu, Zhi-Hong; Liu, Sijiu et al. (2016) Novel Anticancer Agents Based on Targeting the Trimer Interface of the PRL Phosphatase. Cancer Res 76:4805-15|
|Song, Gyun Jee; Jung, Myungsu; Kim, Jong-Heon et al. (2016) A novel role for protein tyrosine phosphatase 1B as a positive regulator of neuroinflammation. J Neuroinflammation 13:86|
|Hamerman, Jessica A; Pottle, Jessica; Ni, Minjian et al. (2016) Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases. Immunol Rev 269:212-27|
|Richine, B M; Virts, E L; Bowling, J D et al. (2016) Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Leukemia 30:2094-2097|
|Zhang, Ruo-Yu; Yu, Zhi-Hong; Zeng, Lifan et al. (2016) SHP2 phosphatase as a novel therapeutic target for melanoma treatment. Oncotarget :|
|Maeshima, Keisuke; Stanford, Stephanie M; Hammaker, Deepa et al. (2016) Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 1:|
Showing the most recent 10 out of 113 publications