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

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

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA. Electronic address: mccormic@cc.ucsf.edu.

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.

PMID:
26590425
DOI:
10.1016/j.cell.2015.10.041
[Indexed for MEDLINE]
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