title: Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer.
abstract: Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.
authors.affiliation: From the Curriculum in Genetics and Molecular Biology,; Lineberger Comprehensive Cancer Center.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Rasmussen
authors.affiliation: From the Curriculum in Genetics and Molecular Biology,; Lineberger Comprehensive Cancer Center.
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Wright
authors.affiliation: Lineberger Comprehensive Cancer Center,; Curriculum in Toxicology.
authors.forename: Samira A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: From the Curriculum in Genetics and Molecular Biology,; Lineberger Comprehensive Cancer Center.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hacker
authors.affiliation: Lineberger Comprehensive Cancer Center.
authors.forename: Zufan
authors.initials: Z
authors.lastname: Debebe
authors.affiliation: Lineberger Comprehensive Cancer Center.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Sendor
authors.affiliation: Lineberger Comprehensive Cancer Center.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Walker
authors.affiliation: Lineberger Comprehensive Cancer Center,; Department of Cell Biology and Physiology, and.
authors.forename: Michael Ben
authors.initials: MB
authors.lastname: Major
authors.affiliation: the Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Green
authors.affiliation: the Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
authors.affiliation: Lineberger Comprehensive Cancer Center,; Departments of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and. Electronic address: Rathmell@med.unc.edu.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
mesh_terms: D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009363:Neoplasm Proteins; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors
keywords: Cancer; RCC; Receptor Tyrosine Kinase; Renal Cell Carcinoma; Ror2; Signaling; Wnt Signaling; Wnt3a; β-Catenin
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