Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer

J Biol Chem. 2013 Sep 6;288(36):26301-10. doi: 10.1074/jbc.M113.466086. Epub 2013 Jul 26.

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.

Keywords: Cancer; RCC; Receptor Tyrosine Kinase; Renal Cell Carcinoma; Ror2; Signaling; Wnt Signaling; Wnt3a; β-Catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / immunology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Receptor Tyrosine Kinase-like Orphan Receptors / biosynthesis*
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Wnt Signaling Pathway*
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • AXIN2 protein, human
  • Axin Protein
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Neoplasm Proteins
  • WNT3A protein, human
  • Wnt3A Protein
  • beta Catenin
  • ROR2 protein, human
  • Receptor Tyrosine Kinase-like Orphan Receptors