SHP2 is a target of the immunosuppressant tautomycetin

Sijiu Liu, Zhihong Yu, Xiao Yu, Sheng Xiong Huang, Yinggang Luo, Li Wu, Weihua Shen, Zhenyun Yang, Lina Wang, Andrea M. Gunawan, Rebecca J. Chan, Ben Shen, Zhong Yin Zhang

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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 languageEnglish (US)
Pages (from-to)101-110
Number of pages10
JournalChemistry and Biology
Volume18
Issue number1
DOIs
StatePublished - Jan 28 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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