Title | MEKK2 mediates an alternative β-catenin pathway that promotes bone formation. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Greenblatt MBlake, Shin DYeon, Oh H, Lee K-Y, Zhai B, Gygi SP, Lotinun S, Baron R, Liu D, Su B, Glimcher LH, Shim J-H |
Journal | Proc Natl Acad Sci U S A |
Volume | 113 |
Issue | 9 |
Pagination | E1226-35 |
Date Published | 2016 Mar 01 |
ISSN | 1091-6490 |
Keywords | Animals, beta Catenin, Bone Development, MAP Kinase Kinase Kinase 2, Mice, Organ Size, Osteoblasts, Phosphorylation |
Abstract | Proper tuning of β-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased β-catenin activity have pathologic consequences. In the classical pathway for β-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of β-catenin by glycogen synthase kinase 3β, preventing β-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 β-catenin activation in osteoblasts that is distinct from the canonical WNT pathway. FGF2 activates MEKK2 to phosphorylate β-catenin at serine 675, promoting recruitment of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15). USP15 in turn prevents the basal turnover of β-catenin by inhibiting its ubiquitin-dependent proteasomal degradation, thereby enhancing WNT signaling. Analysis of MEKK2-deficient mice and genetic interaction studies between Mekk2- and β-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 β-catenin activation, and this pathway is a key regulator of bone formation by osteoblasts. |
DOI | 10.1073/pnas.1600813113 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 26884171 |
PubMed Central ID | PMC4780654 |
Grant List | DP5 OD021351 / OD / NIH HHS / United States R01 AR075585 / AR / NIAMS NIH HHS / United States 1DP5OD021351 / OD / NIH HHS / United States |
Related Faculty:
Matthew B. Greenblatt, M.D., Ph.D.