Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction

Abstract

DJ-1 is a highly conserved multifunctional protein linked to both neurodegeneration and neoplasia. Among its various activities is an antioxidant property leading to cytoprotection under oxidative stress conditions. This is associated with the ability to modulate signal transduction events that determine how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy in order to adapt to environmental stimuli and stresses. Alterations in DJ-1 expression or function can disrupt homeostatic signaling networks and initiate cascades that play a role in the pathogenesis of conditions such as Parkinson's disease and cancer. DJ-1 plays a major role in various signaling pathways. Related to its anti-oxidant properties, it mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation. Here, we review the ways through which DJ-1 regulates these pathways, focusing on how its regulation of signal transduction contributes to cellular homeostasis and the pathologic states that result from their dysregulation.

Keywords: ASK1; Cell signaling; DJ-1; Daxx; ERK; JNK; MAPK; Oxidative stress; Signal transduction; Trx1; p38.

Fig. 1

DJ-1 activates ERK1/2 signaling pathway. (1) DJ-1, but not its C106S mutant, can bind directly to c-Raf and augment c-Raf phosphorylation at Ser-338, which can then activate MEK and ERK1/2 . (2) DJ-1, but not its L166P mutant, protects cells from oxidative injury by activating ERK1/2 and MEK1/2 . The over-expression of wild-type DJ-1 up-regulates ERK1/2 and MEK1/2 phosphorylation , while knock-down of DJ-1 down-regulates phosphorylated ERK1/2 . (3) Under oxidative conditions, DJ-1, but not its C106S mutant, sequesters the transcription factor p53 away from promoters, resulting in down-regulation of the ERK1/2 inhibitor, DUSP1 . (4) DJ-1 interacts directly with ERK1/2 and enhances the nuclear translocation of ERK1/2, where it can activate and phosphorylate the transcription factor Elk1, leading to increased transcription of superoxide dismutase (SOD) . (5) DJ-1 modulates dopamine (DA) homeostasis through activation of ERK1/2 and the resulting phosphorylation and activation of the transcription factor Nurr1, which regulates the transcription of tyrosine hydroxylase (TH) , . (6) Oxidative stress induced by 6-Hydroxydopamine (6-OHDA) may up-regulate DJ-1 through activation of ERK1/2 , . Positive regulation is indicated by pointed green arrows, and negative regulation is indicated by blunted red arrows. Direct or known regulation is indicated by solid lines; indirect or unknown regulation is indicated by dotted lines. Black dashed arrows indicate translocation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).

Fig. 2

DJ-1 inhibits the ASK1 pathway. (1) DJ-1 inhibits ASK1 activation by preventing the dissociation of Trx1 from ASK1 and by increasing the transcription of Trx1 , . (2) DJ-1 inhibits ASK1 activity through nuclear sequestration of Daxx, an ASK1 activator and a part of the active ASK1 signalosome , , . Nuclear localization of DJ-1 may occur through its interaction with PRAK/MK5 which contains a nuclear localization sequence (NLS) . (3) DJ-1 may regulate ASK1 activity through direct binding , , . Positive regulation is indicated by pointed green arrows, and negative regulation is indicated by blunted red arrows. Direct or known regulation is indicated by solid lines; indirect or unknown regulation is indicated by dotted lines. Black dashed arrows indicate translocation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article).