Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 36, Pages 26301-26310Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.466086
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Funding
- National Institutes of Health [R01 CA121781, T32 ES007126, T32 GM008719, T32 HL069768-09]
- National Institutes of Health/UNC Research Training Service Award [T32-CA009156]
- National Institutes of Health Initiative for Maximizing Student Diversity Training Grants [R25GM055336, NCI-F31CA132543]
- American Cancer Society [RSG-10-192-01]
- Howard Hughes Medical Institute Translational Medicine Program
- Medical Scientist Training Program [T32 GM008719]
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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 beta-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 beta-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 beta-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble beta-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.
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