| First Author | Greenblatt MB | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 9 | Pages | E1226-35 |
| PubMed ID | 26884171 | Mgi Jnum | J:231006 |
| Mgi Id | MGI:5766661 | Doi | 10.1073/pnas.1600813113 |
| Citation | Greenblatt MB, et al. (2016) MEKK2 mediates an alternative beta-catenin pathway that promotes bone formation. Proc Natl Acad Sci U S A 113(9):E1226-35 |
| abstractText | 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 3beta, 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 beta-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. |
