K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling

Cell. 2015 Nov 19;163(5):1237-1251. doi: 10.1016/j.cell.2015.10.041.


K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Calmodulin / metabolism
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Genes, ras
  • Humans
  • Mice
  • Molecular Sequence Data
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Papilloma / metabolism
  • Phorbol Esters / administration & dosage
  • Phosphorylation
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Wnt Signaling Pathway*


  • Calmodulin
  • Fzd8 protein, human
  • KRAS protein, human
  • Phorbol Esters
  • Receptors, Cell Surface
  • prostratin
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)