Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation

Mitogen-activated protein kinases (MAPKs) are activated through cascades or modules consisting of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (M APKKK). Investigating the molecular basis of activation of the c-Jun N-term inal kinase (JNK) subgroup of MAPK by the MAPKKK MEKK2, we found that stron g and specific JNK1 activation by MEKK2 was mediated by the MAPKK JNK kinas e 2 (JNKK2) rather than by JNKK1 through formation of a tripartite complex consisting of MEKK2, JNKK2, and JNK1. No scaffold protein was required far the MEEK2-JNKK2-JNK1 tripartite-complex formation. Expression of JNK1, JNKK 2, and MEKK2 significantly augmented the coprecipitation of, respectively, MEKK2-JNKK2, MEKK2-JNK1, and JNKK2-JNK1, indicating that the interaction of MEKK2, JNKK2, and JNK1 is synergistic. Finally, the JNK1 was activated mor e efficiently in the MEKK2-JNKK2-JNK1 complex than was the JNK1 excluded fr om the complex. Thus, formation of a signaling complex through synergistic interaction of a MAPKKK, a MAPKK, and a MAPK molecule like MEKK2-JNKK2-JNK1 is likely to be responsible for the efficient, specific flow of informatio n via MAPK cascades.