Stress-activated kinases

The failure of antioxidant mechanisms to correct redox disequilibrium could lead to the escalation of oxidative to tier 2. Tier 2 cellular responses are characterized by the activation of cellular signaling pathway such as stress-activated kinases (p38 MAP kinase and JNK) along with activation and nuclear translocation of transcription factors NF-kB and STAT-1. NF-KB-induced transcriptional activation leads to the production of a number of pro-inflammatory cytokines, including the neutrophil chemoattractant IL-8. STAT-1 activation stimulates the increased production of CXC-motif chemokines that function in lymphocyte recruitment and activation. Therefore, tier 2 oxidative responses result in an inflammatory response in the lung. 

Park HS, Park E, Kim MS, Ahn K, Kim lY, Choi EJ (2000) Selenite inhibits the c-Jun N-terminal kinase/stress activated kinase (JNK/SAPK) through a thiol redox mechanism. J Biol Chem 275 2527-2531... 

Benhar, M., Engelberg, D., and Levitzki, A. (2002). ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep 3, 420-425. 

JNK/p38 Stress-activated kinases/UV Phosphorylation, Ser 34, mouse p53 Milne et al. (1995)... 

In contrast, several lines of evidence suggest that the activation of the Ras-Raf-ERKl/2 pathway may oppose JNK-mediated effects with respect to mitochondria-dependent apoptosis (Fig. 4). ERKl/2 can phosphorylate and activate mitogen-and stress-activated kinase 1 (MSKl) and pp90 ribosomal S6 kinase (RSK) [83,84]. RSK can phosphorylate BAD, thereby inhibiting its proapoptotic effects [83]. Furthermore, both RSK and MSKl are potent activators of cyclic adenosine monophosphate (cAMP) element binding protein (CREB), a transcription factor for Blc-2, and therefore important for cell survival [84]. The upregulation or overexpression of Bcl-2 has been reported to be associated with the inactivation of JNK [75,85]. Thus, ERKl/2 activation could ultimately lead to JNK inactivation. Finally, the activation of c-Ras has been shown to result in a suppression of Bax expression, via a mechanism that involved activation of both the ERKl/2 signaling cascade and the phosphatidylinositol-3 -kinase (PI-3)/Akt pathway [80]. 

CP-944,629 is a substituted l,2,4-triazolo[4,3-a]pyridine. This compound was designed as a selective inhibitor of the stress-activated kinase p38a, and was nominated as potential disease-modifying drug for rheumatoid arthritis (RA). Purposeful degradation experiments performed on this compound was analyzed by RP-HPLC with UV detection. Analysis of the solid-state photostability samples indicated a lack of mass balance with an assay value of 25% impurities totaling 18% by total area percent. Closer inspection of the sample revealed imdissolved material in the bottom of the volumetric flask. This case study focuses on the identification of the degradation product that resulted in the undissolved material and source of the lack of mass balance. 

SAPK/JNK pathway. Within the SAPK (stress-activated protein kinase) class, the Jun NT-terminal kinases (JNKs) form a subfamily (SAPK/JNK 1-3). 

CDK, cyclin-dependent kinase ERK, extracellular signal-regulated kinase GRK, G protein receptor kinase JNK, Jun kinase MAP kinase, mitogen activated protein kinase MEK, MAP kinase and ERK kinases RSK, ribosomal S6 kinase, GSK, glycogen synthase kinase SAPK, stress-activated protein kinase SEK, SAPK kinase. 

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). 

PRA protein kinase A SAPR stress-activated protein kinase... 

Iordanov, M. S. et al. Ribotoxic stress response Activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA. Mol. Cell. Biol. 17, 3373, 1997. 

Canesi, L. et al., Signalling pathways involved in the physiological response of mussel hemocytes to bacterial challenge the role of stress-activated p38 MAP kinases, Devel. Compar. Immunol., 26, 325, 2002. 

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