Due to the involvement of SHP 2 ( SH 2 domain‐containing protein‐tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP 2 have been developed. Here, we report that the commonly used SHP 2 inhibitor NSC ‐87877 does not exhibit robust inhibitory effects on growth factor‐dependent MAPK (mitogen‐activated protein kinase) pathway activation and that the recently developed active site‐targeting SHP 2 inhibitors IIB ‐08, 11a‐1, and GS ‐493 show off‐target effects on ligand‐evoked activation/trans‐phosphorylation of the PDGFR β (platelet‐derived growth factor receptor β). GS ‐493 also inhibits purified human PDGFR β and SRC in vitro , whereas PDGFR β inhibition by IIB ‐08 and 11a‐1 occurs only in the cellular context. Our results argue for extreme caution in inferring specific functions for SHP 2 based on studies using these inhibitors.
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