MEKK2 mediates an alternative ß-catenin pathway that promotes bone formation.
Proc Natl Acad Sci U S A
; 113(9): E1226-35, 2016 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-26884171
ABSTRACT
Proper tuning of ß-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased ß-catenin activity have pathologic consequences. In the classical pathway for ß-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of ß-catenin by glycogen synthase kinase 3ß, preventing ß-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 ß-catenin activation in osteoblasts that is distinct from the canonical WNT pathway. FGF2 activates MEKK2 to phosphorylate ß-catenin at serine 675, promoting recruitment of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15). USP15 in turn prevents the basal turnover of ß-catenin by inhibiting its ubiquitin-dependent proteasomal degradation, thereby enhancing WNT signaling. Analysis of MEKK2-deficient mice and genetic interaction studies between Mekk2- and ß-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 ß-catenin activation, and this pathway is a key regulator of bone formation by osteoblasts.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenvolvimento Ósseo
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MAP Quinase Quinase Quinase 2
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Beta Catenina
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2016
Tipo de documento:
Article