K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling
Open accessAbstract
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.
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Mutant KRAS promotes stemness properties in tumor cells by suppressing non-canonical Wnt signaling.
“and stemness properties in tumor cells through its ability to suppress non-canonical Wnt signaling (15).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [15]
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- Authors
- Wang, M.-T., Holderfield, M., Galeas, J., Delrosario, R., To, M. D., Balmain, A., & McCormick, F.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- McCormick, Frank
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 163
- Issue
- 5
- Pages
- 1237-1251
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2175955272
- Cited by
- 196
- References
- 64
- Citations by year
- 2026: 13 · 2025: 4 · 2024: 6 · 2023: 14 · 2022: 18 · 2021: 19 · 2020: 23 · 2019: 17 · 2018: 21 · 2017: 30 · 2016: 27 · 2015: 1
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Lustgarten Foundation
- Daiichi-Sankyo
- National Institutes of Health
- Daiichi Sankyo Europe
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- KRAS, H-Ras, calmodulin, CaMKII, FZD8, pancreatic cancer, tumorigenicity, prostratin, protein kinase C, tumor initiation
- MeSH terms
- Amino Acid Sequence, Animals, Calmodulin, Disease Models, Animal, Female, Humans, Molecular Sequence Data, Pancreatic Neoplasms, Papilloma, Phorbol Esters, Phosphorylation, Protein Binding, Genes, ras, Receptors, Cell Surface, Proto-Oncogene Proteins p21(ras), Animals, Genetically Modified, Cell Line, Tumor, Mice, Wnt Signaling Pathway
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