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.