MEKK2 mediates an alternative [Beta]-catenin pathway that promotes bone formation

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-cate...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-03, Vol.113 (9), p.E1226
Main Authors: Greenblatt, Matthew Blake, Shin, Dong Yeon, Oh, Hwanhee, Lee, Ki-Young, Zhai, Bo, Gygi, Steven P, Lotinun, Sutada, Baron, Roland, Liu, Dou, Su, Bing, Glimcher, Laurie H, Shim, Jae-Hyuck
Format: Article
Language:English
Subjects:
Bones
Homeostasis
Kinases
Phosphorylation
Rodents
Online Access:Get full text
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Summary: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.
ISSN:0027-8424
1091-6490