title: MEKK2 mediates an alternative β-catenin pathway that promotes bone formation.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine Weill Cornell Medicine, New York, NY 10065; lglimche@med.cornell.edu mag3003@med.cornell.edu jas2060@med.cornell.edu.
authors.forename: Matthew Blake
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: Department of Pathology and Laboratory Medicine Weill Cornell Medicine, New York, NY 10065;
authors.forename: Dong Yeon
authors.initials: DY
authors.lastname: Shin
authors.affiliation: Department of Pathology and Laboratory Medicine Weill Cornell Medicine, New York, NY 10065;
authors.forename: Hwanhee
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea; Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea;
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; Department of Physiology Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand; STAR on Craniofacial and Skeletal Disorders, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand;
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215;
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Department of Immunobiology Yale Medical School, New Haven, CT 06520; Vascular Biology and Therapeutics Program, Yale Medical School, New Haven, CT 06520;
authors.forename: Dou
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Immunobiology Yale Medical School, New Haven, CT 06520; Vascular Biology and Therapeutics Program, Yale Medical School, New Haven, CT 06520; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China; Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Medicine, Weill Cornell Medicine, New York, NY 10065 lglimche@med.cornell.edu mag3003@med.cornell.edu jas2060@med.cornell.edu.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.affiliation: Department of Pathology and Laboratory Medicine Weill Cornell Medicine, New York, NY 10065; lglimche@med.cornell.edu mag3003@med.cornell.edu jas2060@med.cornell.edu.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
mesh_terms: D000818:Animals; D001846:Bone Development; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism*; D051379:Mice; D009929:Organ Size; D010006:Osteoblasts / Q000166:cytology; D010766:Phosphorylation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D048730:MAP Kinase Kinase Kinase 2
keywords: MAPK; MEKK2; beta-catenin; bone; osteoblasts