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

Abstract

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.

• Authors: Man-Tzu Wang, Matthew Holderfield, Jacqueline Galeas, Reyno Delrosario, Minh D To, Allan Balmain, Frank McCormick
• Journal: Cell (Cell) Vol. 163 Issue 5 Pg. 1237-1251 (Nov 19 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 26590425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• 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, 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