We previously reported that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) functions as a putative scaffold factor in the JNK mitogen-activated protein kinase (MAPK) cascades. In that study we also found MEK1 and Raf-1, which are involved in the extracellular signal-regulated kinase (ERK) MAPK cascades, bind to JSAP1. Here we have defined the regions of JSAP1 responsible for the interactions with MEK1 and Raf-1. Both of the binding regions were mapped to the COOH-terminal region (residues 1054 -1305) of JSAP1. We next examined the effect of overexpressing JSAP1 on the activation of ERK by phorbol 12-myristate 13-acetate in transfected COS-7 cells and found that JSAP1 inhibits ERK's activation and that the COOH-terminal region of JSAP1 was required for the inhibition. Finally, we investigated the molecular mechanism of JSAP1's inhibitory function and showed that JSAP1 prevents MEK1 phosphorylation and activation by Raf-1, resulting in the suppression of the activation of ERK. Taken together, these results suggest that JSAP1 is involved both in the JNK cascades, as a scaffolding factor, and the ERK cascades, as a suppressor. The MAP kinase (MAPK)1 signaling pathway is an intracellular cascade consisting of MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). Upon stimulation, MAPKKK activates MAPKK by phosphorylation on serine (and/or threonine) residues, which in turn activates MAPK by phosphorylation on threonine and tyrosine residues (1, 2). A variety of MAPK cascades have been identified in organisms from yeast to mammals (3)(4)(5). In mammals, five groups of distinguishable MAPK cascades have been identified so far (6). They include the c-Jun NH 2 -terminal kinase (JNK) (also known as stressactivated protein kinase (SAPK), p38, and extracellular signalregulated kinase (ERK) cascades. The JNK and p38 groups of MAPKs are strongly activated in response to proinflammatory cytokines and environmental stresses (7-10). The ERK group of MAPKs is mostly responsive to mitogenic and differentiation stimuli (2,8). For example, the small G protein Ras is activated by many growth factors, and in turn activates the Raf-MEK-ERK cascades (11). The mammalian MAPK cascades play key roles in a wide array of cellular processes, including proliferation, differentiation, and apoptosis (7-11). Thus, mechanisms should exist to ensure specific and efficient activation of the MAPK cascades in response to extracellular stimuli. The recent identification of putative scaffold proteins in the MAPK cascades could account for one of the mechanisms (6,(12)(13)(14)(15). We proposed previously that JNK/SAPK-associated protein 1 (JSAP1) (also known as JNK-interacting protein 3 (15)) functions as a scaffold factor in the JNK MAPK cascades (14). In the same study, we reported that JSAP1 binds Raf-1 MAPKKK and MEK1 MAPKK, which are involved in the ERK MAPK cascades. Here, we have mapped the MEK1-and Raf-1-binding regions in JSAP1 and examined the effect of JSAP1 on the activation of the ERK MAPK casc...
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