Abstract
SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling. SHP2 is also a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors. We report that tautomycetin (TTN), an immunosuppressor in organ transplantation, and its engineered analog TTN D-1 are potent SHP2 inhibitors. TTN and TTN D-1 block T cell receptor-mediated tyrosine phosphorylation and ERK activation and gain-of-function mutant SHP2-induced hematopoietic progenitor hyperproliferation and monocytic differentiation. Crystal structure of the SHP2TTN D-1 complex reveals that TTN D-1 occupies the SHP2 active site in a manner similar to that of a peptide substrate. Collectively, the data support the notion that SHP2 is a cellular target for TTN and provide a potential mechanism for the immunosuppressive activity of TTN. Moreover, the structure furnishes molecular insights upon which therapeutics targeting SHP2 can be developed on the basis of the TTN scaffold.
| Original language | English |
|---|---|
| Pages (from-to) | 101-110 |
| Number of pages | 10 |
| Journal | Chemistry and Biology |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 28 2011 |
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ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Molecular Biology
- Clinical Biochemistry
- Molecular Medicine
- Pharmacology
Cite this
SHP2 is a target of the immunosuppressant tautomycetin. / Liu, Sijiu; Yu, Zhihong; Yu, Xiao; Huang, Sheng Xiong; Luo, Yinggang; Wu, Li; Shen, Weihua; Yang, Zhenyun; Wang, Lina; Gunawan, Andrea M.; Chan, Rebecca; Shen, Ben; Zhang, Zhong-Yin.
In: Chemistry and Biology, Vol. 18, No. 1, 28.01.2011, p. 101-110.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SHP2 is a target of the immunosuppressant tautomycetin
AU - Liu, Sijiu
AU - Yu, Zhihong
AU - Yu, Xiao
AU - Huang, Sheng Xiong
AU - Luo, Yinggang
AU - Wu, Li
AU - Shen, Weihua
AU - Yang, Zhenyun
AU - Wang, Lina
AU - Gunawan, Andrea M.
AU - Chan, Rebecca
AU - Shen, Ben
AU - Zhang, Zhong-Yin
PY - 2011/1/28
Y1 - 2011/1/28
N2 - SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling. SHP2 is also a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors. We report that tautomycetin (TTN), an immunosuppressor in organ transplantation, and its engineered analog TTN D-1 are potent SHP2 inhibitors. TTN and TTN D-1 block T cell receptor-mediated tyrosine phosphorylation and ERK activation and gain-of-function mutant SHP2-induced hematopoietic progenitor hyperproliferation and monocytic differentiation. Crystal structure of the SHP2TTN D-1 complex reveals that TTN D-1 occupies the SHP2 active site in a manner similar to that of a peptide substrate. Collectively, the data support the notion that SHP2 is a cellular target for TTN and provide a potential mechanism for the immunosuppressive activity of TTN. Moreover, the structure furnishes molecular insights upon which therapeutics targeting SHP2 can be developed on the basis of the TTN scaffold.
AB - SHP2 phosphatase is a positive transducer of growth factor and cytokine signaling. SHP2 is also a bona fide oncogene; gain-of-function SHP2 mutations leading to increased phosphatase activity cause Noonan syndrome, as well as multiple forms of leukemia and solid tumors. We report that tautomycetin (TTN), an immunosuppressor in organ transplantation, and its engineered analog TTN D-1 are potent SHP2 inhibitors. TTN and TTN D-1 block T cell receptor-mediated tyrosine phosphorylation and ERK activation and gain-of-function mutant SHP2-induced hematopoietic progenitor hyperproliferation and monocytic differentiation. Crystal structure of the SHP2TTN D-1 complex reveals that TTN D-1 occupies the SHP2 active site in a manner similar to that of a peptide substrate. Collectively, the data support the notion that SHP2 is a cellular target for TTN and provide a potential mechanism for the immunosuppressive activity of TTN. Moreover, the structure furnishes molecular insights upon which therapeutics targeting SHP2 can be developed on the basis of the TTN scaffold.
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U2 - 10.1016/j.chembiol.2010.10.015
DO - 10.1016/j.chembiol.2010.10.015
M3 - Article
C2 - 21276943
AN - SCOPUS:79251557809
VL - 18
SP - 101
EP - 110
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9448
IS - 1
ER -