ROSmediated signaling

Recent studies of the mechanisms of signal transduction have established several facts about this process. Signaling processes are activated as a response to a change in the cellular environment. The mechanism of signaling often involves MAP-kinase mediated protein phosphorylation cascades, which lead to de novo protein synthesis or other adaptive responses. ROS (H2O2) and ROS-mediated events play an important role in some signaling processes.69-71 Some stressors induce mitochondrial production of H2O2, which may act as a second messenger.

In 1991, Baeuerle and colleagues showed that ROS was involved in NF-kB mediated signal transduction, in which cytokine stressors or H2O2 upreg-ulate the HIV-1 gene in human T-cells.72 Other studies show that H2O2 activates signal transduction in many cell types6873-77 and that H2O2 may act as a messenger in epidermal growth factor (EGF) signaling.78,79 Bae and colleagues inhibited EGF signaling in A431 human epidermal carcinoma cells by electroporating catalase into the cells. They showed that the EGF receptor kinase activity was necessary to induce production of H2O2, but that the 126 amino acid carboxyl terminal tail of EGF receptor was not necessary. Thus, H2O2 signaling may involve inactivation of a protein tyrosine phosphatase.78 Other studies strongly implicate H2O2-mediated phosphatase inactivation in signaling in primary astrocytes.67,68

These observations highlight an important concept in H2O2-mediated signaling which has implications in the larger context of redox active signaling. Figure 26.5 presents a scheme illustrating the central importance of phosphatase inactivation in signaling. Several previous studies provide clear-cut biochemical mechanisms for this process. Denu and Tanner80 rigorously demonstrated that the active sites of some phosphatases have an acid cysteine sulhydryl residue which is rapidly converted to a sulfenic acid residue (-SOH) by H2O2. The sulfenic acid residue is then converted back, at a slower rate, to the sulhydryl by glutathione. Thus, H2O2 rapidly inacti-

Ligand Receptor

/ Cytokines, growth factors, \ I environmental stressors, H2O2, ?/

Membrane

Primary

Signaling

Pathway

Protein

Kinase

Cascade factors?

Secondary Signaling Pathway

Protein

Kinases

(inactive)

Active

Phosphorylated Proteins

Transcription Factors (inactive)

H2O2 generator

Mitochondria NAD(P)H Oxidases ?

Active

Transcription Factors

Figure 26.5 Inactivation and reactivation of phosphatases by H2O2 and glutathione (GSH), respectively, and the importance of this process in regulating stressor-mediated signal transduction. PTP is phosphotyrosine phosphatase. H2O2 may be generated by mitochondria or a plasma membrane oxidase. This scheme was adapted from Figure 26.2.69

vates the phosphatase allowing its target protein to remain phosphorylated and stimulating the kinase cascade. Glutathione eventually reactivates the phosphatase activity, tyrosine phosphate residues are removed from the activated kinases and the phosphorylation cascade ceases (Figure 26.5).

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