JNK/SAPKs

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. 

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. 

The JNK/SAPK proteins bind to the N-terminal transactivation domain of c-Jun protein and phosphorylate the residues Ser63 and Ser73. Consequently, increased transcription activity is observed of genes controlled by c-Jim. 

MEKK-1, ERK, p38, and JNK/SAPK. The results are the phosphorylation of IkB and its dissociation from NFkB, thus permitting the translocation of NFkB to the nucleus, as well as the activation of the AP-1 transcription factors Jun and Fos. 

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)...

Rahaus, M., Desloges, N., and Wolff, M.H. (2005). ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation. J Med Virol 76, 424 133. 

Intracellular signaling can now be visualized in peripheral blood lymphocytes with phosphospecific antibodies to MEK, ERK, p38 MAPK, STAT, JNK/ SAPK, and other signal transducers. This allows pharmacodynamic monitoring of signal transduction agonists or inhibitors (especially when coupled with ex vivo T cell activation by phorbal esters or other agents, which can be performed in whole blood) [42-46]. 

MAPKs are hi ly specific in their selection of substrates. Each member of the two MAPK families phosphorylates different substrates. The JNKs/SAPKs, and also the p38 MAPK, transmit signals mainly in response to cytokines and environmental stress. Growth factors turn on the activation of the p42/p44 class of MAPKs which regulate cell proliferation and drive cell-cycle progression. 

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

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. 

Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A. 1998. The human toll signaling pathway divergence of nuclear factor kB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J. Exp. Med. 187 2097-101... 

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... 

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. 

External stimuli that activate the JNK/SAPK and p38 pathways include osmotic stress, exposure to bacterial toxins, and environmental perturbations like heat, UV, ionizing... 

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