Physical association between ABIN‐2 and MEKK2 results selectively blockage of MEKK2 mediated NF‐kappaB and ERK2 but not p38 or JNK’s activation

Abstract

NF-kappaB can be activated by wide variety of stimuli associated with stress or injury in cells. MEKK/ERK kinase kinase (MEKK) 2/3 belong to the family of serine/threonine kinase, and are regulated by growth factor, cellular stress, and inflammatory cytokines leading to activate ERK, JNK, p38 and NF-kappaB. Here, we presented evidence to show ABIN-2 physically interacted with MEKK2 and MEKK3 through the fourth coil-coil domain of ABIN-2 and N-terminal of MEKK2 and 3. Such interaction abolished MEKK2 mediated IKKbeta, and ERK2, and MEKK3 mediated ERK2 phosphorylation. The inhibitory activity of ABIN-2 to downstream targets of MEKK2 and MEKK3 are very selective, since ERK2 and NF-kappaB activation, but not the activation of JNK or p38 by MEKK2; ERK2 activation, but not the activation of NF-kappaB, JNK or p38 by MEKK3 are blocked. Moreover, we demonstrated ABIN-2 could regulate MEKK2-mediated cell cycle progression, and this effect was dependent on NF-kappaB modulation. These observations suggest that ABIN-2 may participate in multiple signaling pathways to regulate NF-kappaB and ERK2 activation at a selective manner.