SAPK pathway

Curtis, J. and Finkbeiner, S. Sending signals from the synapse to the nucleus possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth. /. Neurosci. Res. 58 88-95,1999. 

An important subgroup of MAP kinases has the transcription factor c-Jun as substrate. These kinases are known as c-Jun NH2 terminal kinases (INK) or, due to their activation by stress signals, as stress activated protein kinases (SAPK). The JNK/SAPK proteins are part of their own protein kinase module that conducts stress signals further at the transcription level, and this signaling pathway is therefore known as the JNK/ SAPK pathway. 

Simon C, Simon M, Vucelic G, Hicks MJ, Plinkert PK, et al. 2001. The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1 dependent promoter activation. Exp. Cell Res. 271 344-55... 

A multitude of input signals can activate these three pathways, and the substrates are very diverse, with substantial overlap in the substrate spectrum, which makes characterization of the pathways difficult. In almost all instances, the stimuli that recruit the JNK/SAPK pathway also recruit the p38 pathway, and these two pathways will therefore be discussed together. 

Cd has been shown to be a specific inducer of c-fos in mesangial cells through activation of Erk kinase, protein kinase C and stress-activated protein kinase (SAPK) pathways [223, 224] and may therefore also play a carcinogenic role in the kidney. 

Figure 12. MAP kinase cascade in neutrophils. The MAP kinase cascade is a series of three protein kinases represented schematically in the left column. Active G-protein [G ] stimulates Ras and PI3K activity, which in turn mediate activation of three MAP kinase cascades, the JNK/SAPK pathway, the ERK1/2 pathway, and the p38 MAP kinase pathway. p38 MAP kinase phosphorylates MK2 and mediates activation of Akt/PKB and Hsp27 phosphorylation. Hsp27 phosphorylation may stimulate actin polymerization and/or myosin contraction.

In contrast, hypoxia did not alter JNK enzyme activity significantly (10), whereas exposure of PC 12 cells to UV hght did increase JNK activity. Thus, this SAPK pathway does not appear to be involved in mediating the response to hypoxia in PC 12 cells. 

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

FIGURE 8.6 Parallel pathways to transcription and the MAP kinase family. The MAP kinases can be classified into three groups, based on the identity of the intermediate residue in their dual phosphorylation motifs (TEY, TGY, or TPY). This classification also defines three distinct signal-transduction pathways indicated as the ERK, the JNK/SAPK, and the p38/HOG pathway, each having unique protein kinases acting upstream. 

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)...

Kiefer F, Tibbies LA, Anafi M, Janssen A, et al. 1996. HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J. 16 7013-7025. 

Crespo P, BUSIELO XR, AARONSON DS. Rac-l dependent stimulation of the JNK/SAPK signaling pathway by Vav. Oncogene 13 455-460,1996. 

ERK and SAPK/JNK often have opposite roles in the regulation of apoptosis. In some cells, such as PC 12 cells, ERK is protective while SAPK/JNK is fadlitative. The effects of ERK, SAPK/JNK on p38 modulation appear to be largely dependent on the context in which these components act. Apoptosis is the result of a critical balance between several MARK pathways. 

Coso OA, Chiariello M, Yu J-C, et al. (1995) The small GTP-binding proteins Racl and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. In Cell, 81 1137-1146. 

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