MEKK2 mediates an alternative β-catenin pathway that promotes bone formation

Proper tuning of beta-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased beta-catenin activity have pathologic consequences. In the classical pathway for beta-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of beta-catenin by glycogen synthase kinase 3 beta, preventing beta-catenin ubiquitination and proteasomal degradation. Here, we have found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2 or MEKK2) mediates an alternative pathway for beta-catenin activation in osteoblasts that is distinct from the canonical WNT pathway. FGF2 activates MEKK2 to phosphorylate eta-catenin at serine 675, promoting recruitment of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15). USP15 in turn prevents the basal turnover of beta-catenin by inhibiting its ubiquitin-dependent proteasomal degradation, thereby enhancing WNT signaling. Analysis of MEKK2-deficient mice and genetic interaction studies between Mekk2- and beta-catenin-null alleles confirm that this pathway is an important physiologic regulator of bone mass in vivo. Thus, an FGF2/MEKK2 pathway mediates an alternative nonclassical pathway for beta-catenin activation, and this pathway is a key regulator of bone formation by osteoblasts.