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Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38) Elk-1 (Cavigelli et al., 1995) Hibi et al., 1993;Dérijard et al., 1994; 1 Corresponding authors 1994; Cavigelli et al., 1995;Gupta et al., 1995;Whitmarsh et al., 1995;Zinck et al., 1995), suggesting that they may Stress-activated protein kinase-3 (SAPK3), a recently be physiological substrates for SAPK1. described MAP kinase family member with a wide-SAPK2 [also termed p38 (Han et al., 1994), p40 spread tissue distribution, was transfected into several (Freshney et al., 1994), RK (Rouse et al., 1994), CSBP mammalian cell lines and shown to be activated in and Mxi2 (Zervos et al., 1995)] activates response to cellular stresses, interleukin-1 (IL-1) and two protein kinases, termed MAP kinase-activated protein tumour necrosis factor (TNF) in a similar manner to kinase-2 (MAPKAP-K2, Rouse et al., 1994), and SAPK1 (also termed JNK) and SAPK2 (also termed MAPKAP-K3 (McLaughlin et al., 1996), which share p38, RK, CSBP and Mxi2). SAPK3 and SAPK2 were 75% amino acid sequence identity, and have similar activated at similar rates in vitro by SAPKK3 (also substrate specificities in vitro (Clifton et al., 1996). termed MKK6), and SAPKK3 was the only activator MAPKAP-K2 and MAPKAP-K3 are activated by the of SAPK3 that was induced when KB or 293 cells were same agonists as SAPK2 (Clifton et al., 1996; McLaughlin exposed to cellular stresses or stimulated with IL-1 or et al., 1996), and their activation is prevented by SB TNF. Co-transfection with SAPKK3 induced SAPK3 203580, a specific inhibitor of SAPK2 which does not activity and greatly enhanced activation in response inhibit SAPK1 or p42 and p44 MAP kinases (Cuenda to osmotic shock. These experiments indicate that et al., 1995). These observations suggest that MAPKAP-SAPKK3 mediates the activation of SAPK3 in several K2 and MAPKAP-K3 are physiological substrates of mammalian cells. SAPK3 and SAPK2 phosphorylated SAPK2. Further experiments employing SB 203580 (and a number of proteins at similar rates, including the other evidence) indicate that SAPK2 mediates the stresstranscription factors ATF2, Elk-1 and SAP1, but induced phosphorylation of the transcription factor CHOP SAPK3 was far less effective than SAPK2 in activating (at Ser78 and Ser81) which enhances its transcriptional MAPKAP kinase-2 and MAPKAP kinase-3. Unlike activity (Wang and Ron, 1996), and that heat shock protein SAPK2, SAPK3 was not inhibited by the drug SB 27 (HSP27) (Stokoe et al., 1992a; 203580. SAPK3 phosphorylated ATF2 at Thr69, Thr71Huot et al., 1995) and the transcription factor CREB (Tan and Ser90, the same residues phosphorylated by et al., 1996) are physiological substrates for MAPKAP-SAPK1, whereas SAPK2 only phosphorylated Thr69 K2/MAPKAP-K3. The phosphorylation of HSP27 appears and Thr71. Our results suggest that cellular functions to enhance the polymerization of actin and is thought to previously attrib...

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