JNK cascades

Conversely, the SAPK/JNK cascade, which is closely associated with apoptosis, is activated by sphingosine (Pyne et al, 1996). Exogenous sphingosine also activates caspase-7in a Bcl-x(L)-sensitive manner wha-eas caspase-8 was unaffected (Nava et al, 2000 Cuvillier et al, 2001). hi addition, sphingosine stimulates p38 MAPK in osteoblast-like cells (Kozawa et al, 2000) but not in oligodendrocytes where is produces lysis (Hida et al, 1999). p38 MAPK is up-stream of MAPKAP kinase-2 and the... 

Rosette, C., and M. Karin (1996). Ultraviolet light and osmotic stress activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 274 1194-1197. 

CBl-dependent apoptosis of primary neurons may involve phospholipase A2-induced release of arachidonic acid, which promotes the activation of cyclooxygenases and lipoxygenases (Chan et al. 2003). This may generate free radicals and lead to lipid peroxidation and cell death. Activation of the JNK cascade may also contribute to this neurotoxic process (Downer et al. 2003) (Table 1). 

Yang, W., Tiffany-Castiglioni, E., Koh, H.C., and Son, l.H. 2009. Paraquat activates the IREl/ ASKl/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. Toxicology Letters, 191(2-3), 203-210. doi 10.1016/j.toxlet.2009.08.024. 

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

Pyne, S., Chapman, J., Steele, L. and Pyne, N.J., 1996, Sphingomyehn-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle. Ear. J. Biochem. 237 819-826. 

Bogoyevitch MA, Boehm I, Oakley A, et al. Targeting the JNK MAPK cascade for inhibition basic science and therapeutic potential. 

Pretreatment of neurons by flavonoids (epicatechin and its 3 -D-methylether, kaempferol) strongly inhibits cell death induced by oxidized low-density lipoproteins (ox-LDL) without reduction of ox-LDL uptake or intracellular oxidative stress. Cell protection is selectively correlated to inactivation of JNK, thus suggesting that, irrespective of their H-atom donating activity, flavonoids can selectively attenuate a pro-apoptotic signaling cascade involving MAPKs. 

Fig. 3.4 The JNK/SAPK signaling pathway various signals including cytokines activate the MAP kinases. The JNK/SAPK cascade is activated in response to inflammatory cytokines, heat shock or ultraviolet radiation. Two small G proteins, Rac and cdc42, mediate the activation of the MAP kinases. After activation, cdc42 binds to and activates PAK65 protein kinase. This results in the activation of MEKK, which eventually phosphorylates JNK/SAPK that migrates to the nucleus and activates the expression of several genes specifically the phosphorylation of c-Jun (see Color Insert)...

Fig. 4.1 Growth-factor signals are channelled in the Raf/Ras pathway, resulting in cellular proliferation and differentiation, whereas stress and cytokine signals are directed via MAPKKKs and MAPKKs to JNKs 1 and 2 and the p38 MAP kinase. They cause growth inhibition and apoptosis. Second messengers, such as lipid messengers, may also adress the MAP kinase cascade and elicit specific cellular responses. Included in the scheme are upstream kinases, such as Raf, that in turn activate the MAPKKs (not shown), and eventually the p44 MAPKs 1 and 2 (or ERKs). (This scheme is simple and not complete, because some kinases participating in these signalling pathways are not yet defined.)...

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