Sustained activation of glial cell epidermal growth factor receptor by bis(thiosemicarbazonato) metal complexes is associated with inhibition of protein tyrosine phosphatase activity

Katherine Ann Price, Aphrodite Caragounis, Brett M. Paterson, Gulay Filiz, Irene Volitakis, Colin L. Masters, Kevin J. Barnham, Paul S. Donnelly, Peter J. Crouch, Anthony R. White

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

Bis(thiosemicarbazonato) metal complexes (MII(btsc)) have demonstrated potential neuroprotective activity in cell and animal models of Alzheimer's disease (AD). Metal complexes can activate the epidermal growth factor receptor (EGFR), leading to inhibition of amyloid peptide accumulation in neuronal cells. As glial cells also have an important role in modulating neuronal health and survival in AD, we examined the effect of M II(btsc) on activity of EGFR in an astroglial cell line. Our findings reveal potent activation of glial EGFR by glyoxalbis(N(4)- methylthiosemicarbazonato)CuII] (CuII(gtsm)). Activation of EGFR by CuII(gtsm) involved phosphorylation of multiple tyrosine residues and was mediated by a cognate ligand-independent process involving MII(btsc) inhibition of protein tyrosine phosphatase (PTP) activity. EGFR activation resulted in release of growth factors and cytokines with potential modulatory effects on neuronal function. These studies provide an important insight into the mechanism of action of a neuroprotective M II(btsc) and provide a basis for future studies into this novel approach to AD therapy.

Original languageEnglish
Pages (from-to)6606-6620
Number of pages15
JournalJournal of Medicinal Chemistry
Volume52
Issue number21
DOIs
Publication statusPublished - 12 Nov 2009
Externally publishedYes

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