A Scaffold Protein in the c-Jun NH2-terminal Kinase Signaling Pathways Suppresses the Extracellular Signal-regulated Kinase Signaling Pathways

• Published in: The Journal of biological chemistry 2000-12, Vol.275 (51), p.39815-39818
• Main Authors: Kuboki, Yoshihide, Ito, Michihiko, Takamatsu, Nobuhiko, Yamamoto, Ken-ichi, Shiba, Tadayoshi, Yoshioka, Katsuji
• Format: Article
• Language: English
• Subjects: Animals; COS Cells; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C000403200

We previously reported that c-Jun NH2-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.