Abstract
Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF-induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2-dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases.
Highlights
Shp[2] is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors
This auto-inhibition can be relieved by the association of Shp[2] SRC homology 2 (SH2) domains with docking proteins phosphorylated at tyrosine sites, and this activation process is stimulated by growth factors or cytokines[1]
Fumos exhibited some inhibitory effects on PTP1B, TCPTP, and Shp[1], whose structures are closely related to Shp[2], the values of IC50 are much higher than that of Shp[2], indicating its particular specificity toward Shp[2] (Table 1)
Summary
Shp[2] is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion These results suggest that Fumos can inhibit Shp2dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases. Upregulation of Shp[2] expression has been reported in other human cancers, including breast cancer, liver cancer, gastric cancer, oral cancer, non–small cell lung cancer and thyroid cancer[8,9,10,11,12,13,14] This makes Shp[2] an excellent target for the development of therapeutic drugs. On these controversial reports, Wang proposed that Shp[2] plays dual roles in liver cancer, either suppressing or promoting the development of hepatocellular carcinoma[13]
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