The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis.
Morphogenesis and remodeling of bone involve synthesis of bone matrix by osteoblasts and coordinate resorption of bone by osteoclasts. Defective bone remodeling caused by altered osteoclast activity underlies a multitude of osteopenic disorders. Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized. Here we report that the molecular adapter Grb-2-associated binder-2 (Gab2) associates with RANK and mediates RANK-induced activation of NF-kappaB, Akt and Jnk. Inactivation of the gene encoding Gab2 in mice results in osteopetrosis and decreased bone resorption as a result of defective osteoclast differentiation. We also show that Gab2 has a crucial role in the differentiation of human progenitor cells into osteoclasts. We have thus identified a new, key regulatory scaffold molecule, Gab2, that controls select RANK signaling pathways and is essential for osteoclastogenesis and bone homeostasis.
Wada
Teiji
T
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, A-1030 Vienna, Austria. teiji.wada@imba.oeaw.ac.at
Nakashima
Tomoki
T
Oliveira-dos-Santos
Antonio J
AJ
Gasser
Juerg
J
Hara
Hiromitsu
H
Schett
Georg
G
Penninger
Josef M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016723:Bone Remodeling; D001862:Bone Resorption; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis; D010022:Osteopetrosis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C490894:Gab2 protein, mouse; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse