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

TitleMEKK2 mediates an alternative β-catenin pathway that promotes bone formation.
Publication TypeJournal Article
Year of Publication2016
AuthorsGreenblatt 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
JournalProc Natl Acad Sci U S A
Volume113
Issue9
PaginationE1226-35
Date Published2016 Mar 01
ISSN1091-6490
KeywordsAnimals, 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.

DOI10.1073/pnas.1600813113
Alternate JournalProc Natl Acad Sci U S A
PubMed ID26884171
PubMed Central IDPMC4780654
Grant ListDP5 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.

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