scholarly journals The Orphan Receptor Tyrosine Kinase Ror2 Modulates Canonical Wnt Signaling in Osteoblastic Cells

2005 ◽  
Vol 19 (1) ◽  
pp. 90-101 ◽  
Author(s):  
Julia Billiard ◽  
Deana S. Way ◽  
Laura M. Seestaller-Wehr ◽  
Robert A. Moran ◽  
Annamarie Mangine ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Wnt Signaling ◽  
Receptor Tyrosine Kinase ◽  
Osteoblast Differentiation ◽  
Orphan Receptor ◽  
Osteoblastic Cells ◽  
Related Protein ◽  
Canonical Wnt Signaling ◽  
Opposing Effects ◽  
Canonical Wnt

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 β-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.

Frizzled 6 disruption suppresses osteoblast differentiation induced by nanotopography through the canonical Wnt signaling pathway

2020 ◽  
Vol 235 (11) ◽  
pp. 8293-8303
Author(s):  
Rodrigo Paolo Flores Abuna ◽  
Fabiola Singaretti Oliveira ◽  
Leticia Faustino Adolpho ◽  
Roger Rodrigo Fernandes ◽  
Adalberto Luiz Rosa ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Osteoblast Differentiation ◽  
Wnt Signaling Pathway ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

Beta-Catenin Depended and Independent Effects Induced by Myeloma Cells in Human and Murine Osteoblasts and Osteoblast Progenitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3433-3433
Author(s):  
Francesca Morandi ◽  
Sara Tagliaferri ◽  
Sabrina Bonomini ◽  
Mirca Lazzaretti ◽  
Luca Ferrari ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cell Lines ◽  
Osteoblastic Cells ◽  
Beta Catenin ◽  
Canonical Wnt Signaling ◽  
Osteoprogenitor Cell ◽  
Significant Difference ◽  
Bone Biopsies ◽  
Canonical Wnt ◽  
Osteoblast Progenitors

Abstract Osteoblast impairment occurs within myeloma (MM) cell infiltration into the bone marrow (BM). Wnt signaling is involved in the regulation of osteoblast formation. Canonical Wnt signaling pathway is activated by Wnt 1/3a that induce the activation of GSK3/Axin complex leading to the stabilization and nuclear translocation of beta-catenin that in turn activates the transcription system Lef1/TCF. Recently it has been reported that MM cells produce the Wnt inhibitors DKK-1 demonstrating a correlation between its expression and the presence of bone lesions in MM patients. However the effect of MM cells on Wnt signaling cascade in osteoblasts and osteoblast progenitors has not been investigated. To clarify this issue, first we checked DKK-1 production by human myeloma cell lines (HMCLs), purified CD138+ MM cells and BM plasma of MM patients by PCR and ELISA. Following we performed a co-culture system with HMCLs or CD138+ MM cells and either human osteoblast line (HOBIT) and with BM osteoprogenitor cells (PreOB) obtained after differentiation from mesenchymal cells or murine osteoprogenitor cell lines C2C12 and MC3T3. Both DKK-1 positive HMCLs (XG-1 and JJN3) and negative ones (RPMI-8226, OPM-2) have been used in co-culture as well as DKK-1 positive and negative purified CD138+ MM cells. Similarly we tested the effect of BM plasma of MM patients positive and negative for DKK-1 production on both human and murine cells. Wnt signaling in osteoblasts and osteoblast progenitors was evaluated either at mRNA level by specific human and murine Wnt Array kits and by quantitative PCR or at protein one by Western blot analysis for GSK3b/Axin and LEF-1/TCF expression. We evaluated active de-phosphorylated beta-catenin and inactive phosphorilated one by westernblot and by ELISA in cytosolic and nuclear extracts. DKK-1 median levels detected in the conditioned media of XG-1 and JJN3, MM cells and in BM plasma of DKK-1 positve MM patients were 0.60 ng/mL and 0.38 and 8.84 (range: 1.55–91) ng/mL respectively. Any significant inhibitory effect on WNT signaling and active beta-catenin expression and levels was not observed in HOBIT and human PreOB after co-culture with both HMCLs and MM cells or BM plasma independently to DKK-1 expression. On the contrary DKK-1 positive MM cells or BM plasma suppressed active beta-catenin expression in murine osteoprogenitor cell lines in presence of BMP-2. Consistently Wnt3a stimulation as well as anti-DKK-1 abs. did not restore the inhibitory effects on osteoblast formation and differentiation induced by MM cells in human PreOB. Consistently any significant difference was not detected on beta-catenin expression by stromal/osteoblastic cells on bone biopsies by immunohistochemistry between osteolytic (n°=10) and non-osteolytic (N°=10) MM patients. The different behavior between human and murine osteoblastic cells was further investigated. We found that both cells expressed significant levels of active beta-catenin however DKK-1 suppressed active nuclear and cytosol beta-catenin at concentration of 20–30 ng/mL in C2C12 and MC3T3 whereas only DKK-1 concentrations higher to 500 ng/mL are able to inhibited beta-catenin in HOBIT and human PreOB as well as osteoblast formation and differentiation in human BM cultures. In conclusion our data indicate that MM cells block canonical Wnt signaling in murine osteoblastic cells but not in human osteoblasts and osteoblast progenitors. Beta-catenin independent mechanisms could be involved in DKK-1 mediated bone destruction in MM patients.

scholarly journals Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

2016 ◽  
Vol 291 (26) ◽  
pp. 13730-13742 ◽  
Author(s):  
Eva-Maria Brinkmann ◽  
Benjamin Mattes ◽  
Rahul Kumar ◽  
Anja I. H. Hagemann ◽  
Dietmar Gradl ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Related Protein ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

Nuclear factor I‐C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling

2017 ◽  
Vol 31 (5) ◽  
pp. 1939-1952 ◽  
Author(s):  
Jie Zhou ◽  
Shan Wang ◽  
Qi Qi ◽  
Xiaoyue Yang ◽  
Endong Zhu ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Osteoblast Differentiation ◽  
Nuclear Factor ◽  
Canonical Wnt Signaling ◽  
Factor I ◽  
Nuclear Factor I ◽  
Canonical Wnt

scholarly journals Ectopic repression of receptor tyrosine kinase–like orphan receptor 2 inhibits malignant transformation of ovarian cancer cells by reversing epithelial–mesenchymal transition

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770162 ◽  
Author(s):  
Ying Xu ◽  
Yan-Hui Ma ◽  
Ying-Xin Pang ◽  
Zhe Zhao ◽  
Jing-Jing Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Epithelial Mesenchymal Transition ◽  
Orphan Receptor ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues ◽  
Canonical Wnt

Receptor tyrosine kinase–like orphan receptor 2 is an enzyme-linked receptor which specifically modulates WNT5A signaling and plays an important role in tumorigenesis, invasion, and metastasis; however, the precise role of receptor tyrosine kinase–like orphan receptor 2 in cancer is controversial. The purpose of this study was to investigate the expression and role of receptor tyrosine kinase–like orphan receptor 2 in ovarian carcinoma and clarify the biological functions and interactions of receptor tyrosine kinase–like orphan receptor 2 with non-canonical Wnt pathways in ovarian cancer. The result of the human ovary tissue microarray revealed that the receptor tyrosine kinase–like orphan receptor 2–positive rate increased in malignant epithelial ovarian cancers and was extremely higher in the metastatic tumor tissues, which was also higher than that in the malignant ovarian tumor tissues. In addition, high expression of receptor tyrosine kinase–like orphan receptor 2 was closely related with ovarian cancer grading. The expression of receptor tyrosine kinase–like orphan receptor 2 protein was higher in SKOV3 and A2780 cells than OVCAR3 and 3AO cells. Knockdown of receptor tyrosine kinase–like orphan receptor 2 inhibited ovarian cancer cell proliferation, migration, invasion, and induced morphologic as well as digestive state alterations in stably transfected SKOV3 cells. Detailed study further revealed that silencing of receptor tyrosine kinase–like orphan receptor 2 reversed the epithelial–mesenchymal transition and inhibited non-canonical Wnt signaling. Our findings suggest that receptor tyrosine kinase–like orphan receptor 2 may be an important regulator of epithelial–mesenchymal transition, primarily regulated the non-canonical Wnt signaling pathway in ovarian cancer cells, and may display a promising therapeutic target for ovarian cancer.

scholarly journals Receptor Tyrosine Kinase-like Orphan Receptor 2 (Ror2) Expression Creates a Poised State of Wnt Signaling in Renal Cancer

2013 ◽  
Vol 288 (36) ◽  
pp. 26301-26310 ◽  
Author(s):  
Neal R. Rasmussen ◽  
Tricia M. Wright ◽  
Samira A. Brooks ◽  
Kathryn E. Hacker ◽  
Zufan Debebe ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Wnt Signaling ◽  
Renal Cancer ◽  
Receptor Tyrosine Kinase ◽  
Orphan Receptor

scholarly journals A switch from noncanonical to canonical Wnt signaling stops neuroblast migration through a Slt–Robo and RGA-9b/ARHGAP–dependent mechanism

2021 ◽  
Vol 118 (12) ◽  
pp. e2013239118
Author(s):  
Lorenzo Rella ◽  
Euclides E. Fernandes Póvoa ◽  
Jonas Mars ◽  
Annabel L. P. Ebbing ◽  
Luc Schoppink ◽  
...  
Keyword(s):  
Cell Migration ◽  
Wnt Signaling ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Vertebrate Development ◽  
Canonical Wnt Signaling ◽  
Neuroblast Migration ◽  
Opposing Effects ◽  
Canonical Wnt

Members of the Wnt family of secreted glycoproteins regulate cell migration through distinct canonical and noncanonical signaling pathways. Studies of vertebrate development and disease have shown that these pathways can have opposing effects on cell migration, but the mechanism of this functional interplay is not known. In the nematode Caenorhabditis elegans, a switch from noncanonical to canonical Wnt signaling terminates the long-range migration of the QR neuroblast descendants, providing a tractable system to study this mechanism in vivo. Here, we show that noncanonical Wnt signaling acts through PIX-1/RhoGEF, while canonical signaling directly activates the Slt–Robo pathway component EVA-1/EVA1C and the Rho GTPase–activating protein RGA-9b/ARHGAP, which are required for migration inhibition. Our results support a model in which cross-talk between noncanonical and canonical Wnt signaling occurs through antagonistic regulation of the Rho GTPases that drive cell migration.

Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) Is Expressed in Low Grade NHL and B-CLL and Activates the Non Canonical Wnt Pathway

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3748-3748
Author(s):  
Federica Gibellini ◽  
Colby M Chapman ◽  
Yair Herishanu ◽  
Berengere Vire ◽  
Keyvan Keyvanfar ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Lines ◽  
Receptor Tyrosine Kinase ◽  
Surface Expression ◽  
Orphan Receptor ◽  
Low Grade ◽  
Beta Catenin ◽  
Primary Cells ◽  
Canonical Wnt

Abstract ROR-1, an orphan receptor tyrosine kinase (RTK) carrying an extracellular WNT binding motif, is highly expressed in many tissues during development. Expression of ROR-1 in lymphoid cells has first been noted in a gene expression profiling study of B-cell chronic lymphocytic leukemia (B-CLL), where ROR-1 was expressed in CLL cells but not in diffuse large B-cell lymphoma or in normal B-cells (Rosenwald, 2001). B-CLL is the most common type of leukemia in western countries and is characterized by an accumulation of mature B lymphocytes in the blood and lymphoid tissues. The prolonged survival of the malignant cells in-vivo is dependent on signals derived from the microenvironment. ROR-1 recently has been implicated in mediating stroma dependent survival signals, with WNT5a being a putative ligand for ROR-1 (Fukuda, 2008). In addition, an RNAi screen identified ROR-1 as a tyrosine kinase with anti-apoptotic effects in Hela cells (MacKeigan, 2005). With this background, we have further examined the role of ROR-1 in the survival of B-cell malignancies. We first characterized ROR-1 surface expression by flow cytometry on various lymphoid cell lines and primary cells. We found ROR-1 was highly expressed in mantle cell lymphoma (MCL) cell lines and moderately expressed in the CLL derived EBV positive cell line MEC-1. In contrast, cell lines derived from other B-cell (BJAB, SUDHL-4) and T-cell (Jurkat) malignancies had no ROR-1 expression. Moreover, ROR-1 was highly expressed in primary MCL cells (n= 5) and in follicular lymphoma (n=1). Comparable levels of expression were also detected in CLL cells independent of IgVH mutation status (IgVH unmutated: n=11; IgVH mutated: n= 8). To investigate whether and how ROR-1 could activate intracellular signaling pathways, we chose a monoclonal antibody to induce ROR-1 activation through receptor dimerization. In response to antibody binding, ROR-1 was tyrosine phosphorylated within minutes in a dose dependent manner in MCL cell lines and in primary CLL and MCL cells. Intriguingly, the MCL cell line UPN-1, bearing high ROR-1 surface expression (specific MFI ratio of 19), showed constitutive ROR-1 phosphorylation that further increased after crosslinking. Several studies on ROR-2, the closest ROR-1 homolog, reported activation of the non-canonical WNT signaling pathway and c-Jun N-terminal kinase (JNK) activation. We therefore investigated whether ROR-1 cross-linking could activate JNK and/or lead to stabilization of beta-catenin, the main mediator of canonical WNT signaling. Indeed, we detected JNK phosphorylation in MCL cell lines and in primary CLL cells, while we could not detect beta-catenin activation. In conclusion, ROR-1 surface expression is high in MCL cell lines and primary cells from CLL, MCL and FL patients. ROR-1 crosslinking leads to ROR-1 phosphorylation in both cell lines and primary cells followed by activation of the non-canonical WNT/JNK pathway. Our findings suggest that ROR-1, which plays important roles in embryonic development and organogenesis, could play an important role in the pathogenesis of low grade lymphomas and B-CLL.

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