Fluctuations of cellular, available zinc modulate insulin signaling via inhibition of protein tyrosine phosphatases.
Extracellular zinc ions are effectors of many signaling pathways in mammalian cells, including the insulin/IGF-1 pathway. Molecular targets of zinc are intracellular, however, because otherwise ineffective zinc concentrations alter the extent of protein phosphorylation only in the presence of the ionophore pyrithione. The tight inhibition of protein tyrosine phosphatases by zinc (nanomolar inhibition constants) is likely responsible for the known insulinomimetic effects of zinc ions, which increase net phosphorylation of the insulin/IGF-1-receptors and activate their signaling cascades. More importantly, not only do extracellular zinc ions affect signal transduction, but growth factors induce cellular zinc fluctuations that are of sufficient magnitude to inhibit protein tyrosine phosphatases. In conclusion, a pool of cellular, available zinc participates in phosphorylation/dephosphorylation cascades, suggesting the existence of a cellular signaling system based on zinc as a second messenger.
Haase
Hajo
H
Center for Biochemical and Biophysical Sciences and Medicine, Department of Pathology, Harvard Medical School, Cambridge, MA 02115, USA. hhaase@ukaachen.de
Maret
Wolfgang
W
D000818:Animals; D002460:Cell Line; D005456:Fluorescent Dyes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015363:Quinolones / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity; D014105:Tosyl Compounds / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D005456:Fluorescent Dyes; D007328:Insulin; D015363:Quinolones; D014105:Tosyl Compounds; D007334:Insulin-Like Growth Factor I; D017027:Protein Tyrosine Phosphatases; D015032:Zinc; C084731:zinquin