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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents* / chemistry
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Antineoplastic Agents* / pharmacology
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Drug Discovery*
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Enzyme Activation / drug effects
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Enzyme Inhibitors* / chemistry
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Enzyme Inhibitors* / pharmacology
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ErbB Receptors / metabolism
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HeLa Cells
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Humans
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Hydroxamic Acids* / chemistry
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Hydroxamic Acids* / pharmacology
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MAP Kinase Signaling System / drug effects*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Oncogene Protein p21(ras) / metabolism
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Paxillin / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Pyridones* / chemistry
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Pyridones* / pharmacology
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Hydroxamic Acids
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PXN protein, human
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Paxillin
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Pyridones
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fumosorinone
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EGFR protein, human
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ErbB Receptors
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Oncogene Protein p21(ras)