title: SHP2 is a target of the immunosuppressant tautomycetin.
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 SHP2⋅TTN 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.
authors.affiliation: Department of Biochemistry Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sijiu
authors.initials: S
authors.lastname: Liu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yu
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Sheng-Xiong
authors.initials: SX
authors.lastname: Huang
authors.forename: Yinggang
authors.initials: Y
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Weihua
authors.initials: W
authors.lastname: Shen
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D019169:Jurkat Cells; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011714:Pyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D007166:Immunosuppressive Agents; D008055:Lipids; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; C058744:tautomycetin; D014443:Tyrosine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11