title: The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells.
abstract: Ror2 is an orphan receptor tyrosine kinase that plays crucial roles in developmental morphogenesis, particularly of the skeleton. We have identified human Ror2 as a novel regulator of canonical Wnt signaling in osteoblastic (bone-forming) cells with selective activities, enhancing Wnt1 but antagonizing Wnt3. Immunoprecipitation studies demonstrated physical interactions between human Ror2 and mammalian Wnt1 and Wnt3. Functionally, Ror2 antagonized Wnt1- and Wnt3-mediated stabilization of cytosolic beta-catenin in osteoblastic cells. However, Ror2 had opposing effects on a more distal step of canonical Wnt signaling: it potentiated Wnt1 activity but inhibited Wnt3 function as assessed by changes in Wnt-responsive reporter gene activity. Despite binding to Ror2, neither Wnt1 nor Wnt3 altered receptor activity as assessed by levels of Ror2 autophosphorylation. The ability of Ror2 to regulate canonical Wnt signaling in osteoblastic cells should have physiological consequences in bone, because Wnt signaling is known to modulate osteoblast survival and differentiation. Expression of Ror2 mRNA was highly regulated in a biphasic manner during human osteoblast differentiation, being virtually undetectable in pluripotent stem cells, increasing 300-fold in committed preosteoblasts, and disappearing again in osteocytes. Furthermore, Ror2 expression in osteoblasts was suppressed by the Wnt antagonist, secreted frizzled-related protein 1. The regulated expression of Ror2 during osteoblast differentiation, its inverse expression pattern with secreted frizzled-related protein 1, and its ability to modulate Wnt signaling in osteoblastic cells suggest that Ror2 may regulate bone formation.
authors.affiliation: Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. billiaj@wyeth.com
authors.forename: Julia
authors.initials: J
authors.lastname: Billiard
authors.forename: Deana S
authors.initials: DS
authors.lastname: Way
authors.forename: Laura M
authors.initials: LM
authors.lastname: Seestaller-Wehr
authors.forename: Robert A
authors.initials: RA
authors.lastname: Moran
authors.forename: Annamarie
authors.initials: A
authors.lastname: Mangine
authors.forename: Peter V N
authors.initials: PV
authors.lastname: Bodine
mesh_terms: D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D051176:beta Catenin; D000099274:Frizzled-Related Proteins
chemical_list: D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495247:WNT1 protein, human; C555507:WNT3 protein, human; C495246:Wnt1 protein, mouse; C555508:Wnt3 protein, mouse; C078717:ROR2 protein, human