Genetic lesions in SHP-2, a protein tyrosine phosphatase that plays an overall positive role in hematopoietic cell development and function, have been identified in various childhood leukemias. These mutations cause hyperactivation of its catalytic activity [referred as to gain-of-function (GOF) mutations]. Recent studies suggest that the SHP-2 GOF mutations play a causal role in the leukemogenesis. However, the molecular mechanisms by which the SHP-2 mutations induce these diseases are not well understood. Lack of such knowledge is an important barrier to a rational design of new therapeutics for the related diseases. The objective of this application is to determine what acquired functions of the GOF mutant SHP-2 contribute to hematopoietic malignancies. The central hypothesis of the application is that although GOF mutations result in hyperactivation of catalytic activity, enhanced catalytic activity alone is not sufficient for the mutant SHP-2 to induce hematopoietic malignancies;altered protein-interacting capability (and thus substrate specificity) also plays a vital role. This hypothesis has been formulated on the basis of preliminary data produced in our laboratory. Firstly, SHP-2 functions in IL-3-induced signaling and cellular responses in both catalytic-dependent and -independent manners. The catalytic-independent function promotes IL-3 signaling. Secondly, a 5-to-6 fold access of wild-type SHP-2 in hematopoietic stem/progenitor cells compromises, rather than increases, hematopoietic potential due to accelerated dephosphorylation of STAT5. Thirdly, E76K, the most frequent SHP-2 mutation found in leukemias, also alters physical and functional interactions of SHP-2 with signaling partners Gab2 and STAT5, leading to enhanced downstream signaling. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following three Aims. 1) Characterize phosphoprotein interaction property of the GOF mutant SHP-2. 2) Define the mechanisms by which the elevated catalytic activity and the altered protein-interacting capability of the GOF mutant SHP-2 disturb hematopoietic cell signaling. 3) Determine the contribution of elevated catalytic activity and altered protein-interacting capability of the GOF mutant SHP-2 to in vivo leukemogenesis. It is expected that these studies collectively will yield new insight into the underlying mechanisms of the hematopoietic malignancies induced by SHP-2 mutations as well as providing a molecular basis for a future rational design of new therapeutics that specifically target SHP-2 or downstream intermediates for treatment of related diseases. In addition, the results are expected to fundamentally advance the field of cell signaling. Project Narrative: The studies proposed seek to understand the mechanisms of childhood leukemias induced by genetic mutations in SHP-2 tyrosine phosphatase. The information gathered will provide a molecular basis for a future rational design of new therapeutics that specifically target SHP-2 for treatment of related leukemias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068212-09
Application #
8197761
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2002-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Zheng, Hong; Li, Shanhu; Hsu, Peter et al. (2013) Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence. J Biol Chem 288:25727-38
Liu, Wei; Yu, Bing; Xu, Gang et al. (2013) Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11). J Med Chem 56:7212-21
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Yu, Bing; Liu, Wei; Yu, Wen-Mei et al. (2013) Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. Mol Cancer Ther 12:1738-48
Hsu, Peter; Qu, Cheng-Kui (2013) Metabolic plasticity and hematopoietic stem cell biology. Curr Opin Hematol 20:289-94
Shen, Jinhua; Liu, Xia; Yu, Wen-Mei et al. (2011) A critical role of mitochondrial phosphatase Ptpmt1 in embryogenesis reveals a mitochondrial metabolic stress-induced differentiation checkpoint in embryonic stem cells. Mol Cell Biol 31:4902-16
Xu, Dan; Liu, Xia; Yu, Wen-Mei et al. (2011) Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells. J Exp Med 208:1977-88
Xu, Dan; Wang, Siying; Yu, Wen-Mei et al. (2010) A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells. Blood 116:3611-21
Romero-Suarez, Sandra; Shen, Jinhua; Brotto, Leticia et al. (2010) Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis. Aging (Albany NY) 2:504-13

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