Sustained Activation of Glial Cell Epidermal Growth Factor Receptor by Bis(thiosemicarbazonato) Metal Complexes Is Associated with Inhibition of Protein Tyrosine Phosphatase Activity

• Published in: Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6606-6620
• Main Authors: Price, Katherine Ann, Caragounis, Aphrodite, Paterson, Brett M, Filiz, Gulay, Volitakis, Irene, Masters, Colin L, Barnham, Kevin J, Donnelly, Paul S, Crouch, Peter J, White, Anthony R
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Line; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper; Cytokines - metabolism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Glycogen Synthase Kinase 3 - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Medical sciences; Neuroglia - cytology; Neuroglia - drug effects; Neuroglia - metabolism; Neuropharmacology; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pharmacology. Drug treatments; Phosphorylation; Protein Array Analysis; Protein Tyrosine Phosphatases - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptor, Epidermal Growth Factor - metabolism; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9007938

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 MII(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 MII(btsc) and provide a basis for future studies into this novel approach to AD therapy.