Axin forms a complex with MEKK1 and activates c-Jun NH2-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling

Axin negatively regulates the Wnt pathway during axis formation and plays a central role in cell growth control and tumorigenesis, We found that Axin also serves as a scaffold protein for mitogen-activated protein kinase acti vation and further determined the structural requirement for this activatio n. Overexpression of Axin in 293T cells leads to differential activation of mitogen-activated protein kinases, with robust induction for c-Jun NH2-ter minal kinase (JNK)/stress-activated protein kinase, moderate induction for p38, and negligible induction for extracellular signal-regulated kinase, Ax in forms a complex with MEKK1 through a novel domain that we term MEKK1-int eracting domain, MKK4 and MKK7, which act do downstream of MEKK1, are also involved in Axin-mediated JNK activation. Domains essential in Wnt signalin g, i.e, binding sites for adenomatous polyposis coli, glycogen synthase kin ase-3 beta, and beta-catenin, are not required for JNK activation, suggesti ng distinct domain utilization between the Wnt pathway and JNK signal trans duction. Dimerization/oligomerization of Axin through its C terminus is req uired for JNK activation, although MEKK1 is capable of binding C terminus-d eleted monomeric Axin, Furthermore, Axin without the MEKK1-interacting doma in has a dominant-negative effect on JNK activation by wild-type Axin, Our results suggest that Axin, in addition to its function in the Wnt pathway, may play a dual role in cells through its activation of JNK/stress-activate d protein kinase signaling cascade.