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Abstract: The phosphoinositide 3′-kinase (PI3K)/Akt signaling cascade controls cellular processes such as apoptosis and proliferation. Moreover, it is a mediator of insulin effects on target cells and as such is a major regulator of fuel metabolism. The PI3K/Akt cascade was demonstrated to be activated by stressful stimuli, including heat shock and reactive oxygen species (ROS). This minireview focuses on activation of the pathway by exposure of cells to heavy metal ions, Cu2+ and Zn2+. It is hypothesized that stimulation of PI3K/Akt is the molecular mechanism underlying the known insulin-mimetic effects of copper and zinc ions. Following a brief summary of PI3K/Akt signaling and of activation of the cascade by Cu2+ and Zn2+, mechanisms of metal-induced PI3K/Akt activation are discussed with a focus on the role of ROS and of cellular thiols (glutathione, thioredoxin) and protein tyrosine phosphatases in Cu2+ and Zn2+ signaling. Finally, consequences of metal-induced PI3K/Akt activation are discussed, focusing on the modulation of FoxO-family transcription factors by Cu2+ and Zn2+. [Copyright &y& Elsevier]

Copper is implicated in metabolic disorders, such as Wilson''s disease or Alzheimer''s disease. Analysis of signaling pathways regulating cellular survival and function in response to a copper stress is crucial for understanding the pathogenesis of such diseases. Exposure of human skin fibroblasts or HeLa cells to Cu2+ resulted in a dose- and time-dependent activation of the antiapoptotic kinase Akt/protein kinase B, starting at concentrations as low as 3 μM. Only Cu(II), but not Cu(I), had this effect. Activation of Akt was accompanied by phosphorylation of a downstream target of Akt, glycogen synthase kinase-3. Inhibitors of phosphoinositide-3-kinase (PI3K) completely blocked activation of Akt by Cu2+, indicating a requirement of PI3K for Cu2+-induced activation of Akt. Indeed, cellular PI3K activity was strongly enhanced after exposure to Cu2+. Copper ions may lead to the formation of reactive oxygen species, such as hydrogen peroxide. Activation of Akt by hydrogen peroxide or growth factors is known to proceed via the activation growth factor receptors. In line with this, pretreatment with inhibitors of growth factor receptor tyrosine kinases blocked activation of Akt by hydrogen peroxide and growth factors, as did a src-family tyrosine kinase inhibitor or the broad-spectrum tyrosine kinase inhibitor genistein. Activation of Akt by Cu2+, however, remained unimpaired, implying (i) that tyrosine kinase activation is not involved in Cu2+ activation of Akt and (ii) that activation of the PI3K/Akt pathway by Cu2+ is initiated independently of that induced by reactive oxygen species. Comparison of the time course of the oxidation of 2′,7′-dichlorodihydrofluorescein in copper-treated cells with that of Akt activation led to the conclusion that production of hydroperoxides cannot be an upstream event in copper-induced Akt activation. Rather, both activation of Akt and generation of ROS are proposed to occur in parallel, regulating cell survival after a copper stress. [Copyright &y& Elsevier]