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Homodimerization of Ror2 Tyrosine Kinase Receptor Induces 14-3-3β Phosphorylation and Promotes Osteoblast Differentiation and Bone Formation

Women’s Health and Musculoskeletal Biology (Y.L., P.V.N.B., J.B.), Wyeth Research, Collegeville, Pennsylvania 19426; and Biological Technologies (J.F.R.), Wyeth Research, Cambridge, Massachusetts 02140

Address all correspondence and requests for reprints to: Julia Billiard, Ph.D., Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: billiaj{at}wyeth.com.

Ror2 receptor plays a key role in bone formation, but its signaling pathway is not completely understood. We demonstrate that Ror2 homodimerizes at the cell surface, and that dimerization can be induced by a bivalent antibody. Antibody-mediated dimerization causes receptor autophosphorylation and induces functional consequences of its signaling, including osteogenesis in mesenchymal stem cells and bone formation in organ culture. We further show that Ror2 associates with and phosphorylates 14-3-3β scaffold protein. Endogenous Ror2 binds 14-3-3β in U2OS osteosarcoma cells, and purified intracellular domain of Ror2 interacts with 14-3-3β in vitro. 14-3-3β Is tyrosine phosphorylated in U2OS cells, and this phosphorylation is inhibited by down-regulating Ror2 and enhanced by overexpressing the kinase. Purified Ror2 phosphorylates 14-3-3β in vitro, confirming 14-3-3β as the first identified Ror2 substrate. Down-regulating 14-3-3β potentiates osteoblastogenesis in mesenchymal stem cells and increases bone formation in calvarial cultures, indicating that 14-3-3β exerts a negative effect on osteogenesis. This raises a possibility that Ror2 induces osteogenic differentiation, at least in part, through a release of the 14-3-3β-mediated inhibition. Our research forms a foundation for several new areas of investigation, including the molecular regulation of 14-3-3 by tyrosine phosphorylation and the role of this scaffold in osteogenesis.