Sustained activation of glial cell epidermal growth factor receptor by bis(thiosemicarbazonato) metal complexes is associated with inhibition of protein tyrosine phosphatase activity.
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.
Price
Katherine Ann
KA
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Caragounis
Aphrodite
A
Paterson
Brett M
BM
Filiz
Gulay
G
Volitakis
Irene
I
Masters
Colin L
CL
Barnham
Kevin J
KJ
Donnelly
Paul S
PS
Crouch
Peter J
PJ
White
Anthony R
AR
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
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