title: Sustained activation of glial cell epidermal growth factor receptor by bis(thiosemicarbazonato) metal complexes is associated with inhibition of protein tyrosine phosphatase activity.
abstract: Bis(thiosemicarbazonato) metal complexes (M(II)(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)Cu(II)] (Cu(II)(gtsm)). Activation of EGFR by Cu(II)(gtsm) involved phosphorylation of multiple tyrosine residues and was mediated by a cognate ligand-independent process involving M(II)(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.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Katherine Ann
authors.initials: KA
authors.lastname: Price
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Brett M
authors.initials: BM
authors.lastname: Paterson
authors.forename: Gulay
authors.initials: G
authors.lastname: Filiz
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003300:Copper; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D040081:Protein Array Analysis; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D056831:Coordination Complexes; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C545536:glyoxalbis(N(4)-methylthiosemicarbazonato)copper(II); D003300:Copper; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D017027:Protein Tyrosine Phosphatases