Regulation of Signal Transduction by DJ-1

Abstract

The ability of DJ-1 to modulate signal transduction has significant effects on how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy to adapt to changing environmental stimuli and stresses. Perturbations of DJ-1 levels or function can disrupt the equilibrium of homeostatic signaling networks and set off cascades that play a role in the pathogenesis of conditions such as cancer and Parkinson's disease.DJ-1 plays a major role in various pathways. It mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. It attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation as well as by inhibiting mitogen-activated protein kinase kinase kinase 1 (MEKK1/MAP3K1) activation of downstream apoptotic cascades. It also modulates autophagy through the ERK, Akt, or the JNK/Beclin1 pathways. In addition, DJ-1 regulates the transcription of genes essential for male reproductive function, such as spermatogenesis, by relaying nuclear receptor androgen receptor (AR) signaling. In this chapter, we summarize the ways that DJ-1 regulates these pathways, focusing on how its role in signal transduction contributes to cellular homeostasis and the pathologic states that result from dysregulation.

Keywords: AR; ASK1; Akt; Cell signaling; DJ-1; Daxx; ERK; JNK; MAPK; MEK; MEKK1; PI3K; Raf; Ras; Signal transduction; Trx1; mTOR; p38.

Fig. 8.1. Major signaling pathways regulated by DJ-1

DJ-1 activates the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway to mediate cell survival, proliferation, and autophagy. It can also activate androgen receptor (AR) signaling to induce transcription of genes necessary for male reproductive function. [Activation is indicated by pointed green arrows] DJ-1 can inhibit apoptosis signal-regulating kinase 1 (ASK1) activation as well as MEKK1 activation of downstream apoptotic cascades. [Inhibition is indicated by blunted red arrows] EMT, epithelial-mesenchymal transition

Fig. 8.2. DJ-1 activates ERK1/2 signaling pathway

1. 6-Hydroxydopamine-induced oxidative stress may upregulate DJ-1 through activation of ERK1/2 (Lev et al. 2009) 2. DJ-1, but not its L166P mutant, protects cells from oxidative injury by activating ERK1/2 and MEK1/2 (Gu et al. 2009) 3. DJ-1 mediates dopamine (DA) homeostasis through activation of ERK1/2 and the resulting nuclear translocation of the transcription factor Nurr1 (Lu et al. 2012; Lu et al. 2016) 4. DJ-1 activates the non-canonical MEK/ERK-mTOR pathway to activate autophagy (Gao et al. 2012; Krebiehl et al. 2010) 5. DJ-1 promotes oncogenic potential by activating the SRC/ERK/uPA axis (He et al. 2012) 6. DJ-1 interacts directly with ERK1/2 and may enhance the nuclear translocation of ERK1/2, where it can phosphorylate Elk1, leading to increased SOD expression (Wang et al. 2011) 7. DJ-1, but not its C106S mutant, can bind directly to and phosphorylate c-Raf, which can then activate MEK and ERK1/2 (Takahashi-Niki et al. 2015) 8. DJ-1, but not its L166P mutant, suppresses the expression of PP2A, an inhibitor of MEK1/2 and ERK1/2 family kinases (Gu et al. 2009) 9. DJ-1, but not its C106S mutant, may sequester p53 away from promoters in a DNA-binding affinity-dependent manner, resulting in downregulation of ERK1/2 inhibitor, DUSP1 (Kato et al. 2013) [positive regulation is indicated by pointed arrows, and negative regulation is indicated by blunted arrows. Direct or known regulation is indicated by solid lines; indirect or unknown regulation is indicated by dotted lines]

Fig. 8.3. DJ-1 activates PI3K/AKT1 signaling pathway

1. DJ-1 increases phosphorylated Akt, and activates the PI3k/Akt pathway, which contributes to oncogenesis and neuronal survival (Kim et al. 2005; Yang et al. 2005; Aleyasin et al. 2010; Zhang et al. 2016) 2. Under hypoxic conditions, DJ-1 mediates the activation of HIF1 that regulates the expression of many genes needed for cells to adapt to hypoxic conditions. DJ-1 does this by increasing mTORC activity through PI3k/Akt pathway modulation, decreasing p53 activation, and increasing AMPK activation of mTORC (Vasseur et al. 2009), as well as by inhibiting HIF-VHL interaction through direct binding with VHL (Parsanejad et al. 2014) 3. There may be significant cross talk and feedback regulation between p53, DJ-1, and the Akt pathway. p53 may inhibit DJ-1 activation through phosphorylation (Rahman-Roblick et al. 2008) and may also decrease DJ-1 protein levels through a posttranscriptional route (Vasseur et al. 2012). p53 negatively regulates the IGF-1/PI3k/Akt pathway by increasing the transcription of target genes such as IGF-BP3 or PTEN (Feng 2010), and is also conversely regulated by Akt, which activates the E3 ubiquitin ligase MDM2, a trigger for p53 degradation (Mayo and Donner 2002). Oxidative stress may induce DJ-1-mediated phosphorylation/activation of p53 (Vasseur et al. 2012), a process that may be mediated by active Akt (Zhan et al. 2010). Active p53 may then respond appropriately to stress by activating transcriptional programs (Kruiswijk et al. 2015). In a negative feedback loop, p53 can also decrease DJ-1 levels and attenuate Akt activation, preventing abnormal cellular transformation (Vasseur et al. 2012) 4. PD pathogenic mutants (L166P, D146A) of DJ-1 lose the ability to inhibit GSK-3β through the regulation of the Akt pathway and may contribute to increased tau phosphorylation and PD pathogenesis (Wang et al. 2013) 5. By activating the PI3K/Akt pathway, DJ-1 may increase the activity of downstream transcription factor c-myc to modulate the expression of human telomerase reverse transcriptase (hTERT), which is implicated in cellular differentiation and neoplastic transformation (Sitaram et al. 2009) 6. DJ-1 may play a role in modulating recruitment of Akt to the membrane in an ROS-dependent manner (Aleyasin et al. 2010) 7. DJ-1 binds mRNAs of PI3K/Akt pathway (Akt1, IGF2) and may release them to be translated under oxidative stress (van der Brug et al. 2008) 8. DJ-1 may decrease ceramide-induced autophagy and cell death through its effects on the PI3k/ AKT pathway (Jaramillo-Gomez et al. 2015) 9. DJ-1 may bind PTEN directly in a manner dependent on the redox status of its Cys-106 residue (Kim et al. 2009). And under nitrosative stress, DJ-1 may directly bind and inhibit PTEN activity via transnitrosylation [positive regulation is indicated by pointed arrows, and negative regulation is indicated by blunted arrows. Direct or known regulation is indicated by solid lines; indirect or unknown regulation is indicated by dotted lines]

Fig. 8.4. DJ-1 inhibits the ASK1 pathway

1. DJ-1 inhibits ASK1 activity through nuclear sequestration of Daxx, an ASK1 activator and a part of the active ASK1 signalosome (Junn et al. 2005; Hwang et al. 2013; Karunakaran et al. 2007). Nuclear localization of DJ-1 may occur through its interaction with PRAK/MK5 which contains a nuclear localization sequence (NLS) (Tang et al. 2014) 2. DJ-1 may regulate ASK1 activity through direct binding (Waak et al. 2009; Mo et al. 2010; Cao et al. 2014) 3. DJ-1 inhibits ASK1 activation by preventing the dissociation of Trx1 from ASK1 and also by increasing the transcription of Trx1 (Im et al. 2010; Im et al. 2012) [positive regulation is indicated by pointed arrows, and negative regulation is indicated by blunted arrows. Direct or known regulation is indicated by solid lines; indirect or unknown regulation is indicated by dotted lines]