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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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“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]
Citations
Cites
ras oncogenes in human cancer: a review.
Bos, J. L. (1989) · PubMed · Cited by 5,061
Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., & Nishizuka, Y. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34459-4 · Cited by 4,725
Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C., Jamieson, C., Jones, D. L., Visvader, J., Weissman, I. L., & Wahl, G. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-3126 · Cited by 3,124
TRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and Function
Rao, A., Luo, C. H., & Hogan, P. G. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.707 · Cited by 2,592
(2012) · doi:10.1016/j.jmoldx.2011.08.002 · Cited by 2,567
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471
A Comprehensive Survey of Ras Mutations in Cancer
Prior, I. A., Lewis, P. D., & Mattos, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2612 · Cited by 2,063 · cited 1×
“K-Ras mutations occur at high frequency in pancreatic and colorectal cancers and in lung adenocarcinomas, while N-Ras and H-Ras mutations are far less common (Prior et al., 2012).”
BackgroundSubtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy
Collisson, E. A., Sadanandam, A., Olson, P., Gibb, W. J., Truitt, M., Gu, S., Cooc, J., Weinkle, J., Kim, G. E., Jakkula, L., et al. (2011) · Nature Medicine · doi:10.1038/nm.2344 · Cited by 1,967
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,927
RAS oncogenes: the first 30 years
Malumbres, M., & Barbacid, M. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1097 · Cited by 1,902 · cited 1×
“Furthermore, K-Ras deficiency results in embryonic lethality, whereas N- and H-Ras knockout mice develop normally (Johnson et al., 1997; Koera et al., 1997; Malumbres and Barbacid, 2003).”
BackgroundPonti, D., Costa, A., Zaffaroni, N., Pratesi, G., Petrangolini, G., Coradini, D., Pilotti, S., Pierotti, M. A., & Daidone, M. G. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0626 · Cited by 1,725
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467
A tumorigenic subpopulation with stem cell properties in melanomas
Fang, D., Nguyen, T. K., Leishear, K., Finko, R., Kulp, A. N., Hotz, S., Van Belle, P. A., Xu, X., Elder, D. E., & Herlyn, M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1343 · Cited by 1,280
Structural Basis of Protein Kinase C Isoform Function
Steinberg, S. (2008) · Physiological Reviews · doi:10.1152/physrev.00034.2007 · Cited by 922
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., & Settleman, J. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.022 · Cited by 841
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798
Klee, C. B., & VANAMAN, T. C. (1982) · Advances in protein chemistry · doi:10.1016/s0065-3233(08)60470-2 · Cited by 778
Sasaki, H., Nishizaki, Y., Hui, C.-C., Nakafuku, M., & Kondoh, H. (1999) · Development · doi:10.1242/dev.126.17.3915 · Cited by 715
Powell, A. E., Wang, Y., Li, Y., Poulin, E. J., Means, A. L., Washington, M. K., Higginbotham, J. N., Juchheim, A., Prasad, N., Levy, S. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.042 · Cited by 694
Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer
Sozzi, G., Conte, D., Leon, M., Cirincione, R., Roz, L., Ratcliffe, C., Roz, E., Cirenei, N., Bellomi, M., Pelosi, G., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.02.006 · Cited by 548
Scholl, C., Fröhling, S., Dunn, I. F., Schinzel, A. C., Barbie, D. A., Kim, S. Y., Silver, S. J., Tamayo, P., Wadlow, R. C., Ramaswamy, S., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.017 · Cited by 546
K-ras is an essential gene in the mouse with partial functional overlap with N-rasPreprint
Johnson, L., Greenbaum, D. C., Cichowski, K. M., Mercer, K. L., Murphy, E. A., Schmitt, E. S., Bronson, R. T., Umanoff, H., Edelmann, W., Kucherlapati, R., et al. (1997) · Genes & Development · doi:10.1101/gad.11.19.2468 · Cited by 540
Dankort, D. L., Filenova, E., Collado, M., Serrano, M., Jones, K. D., & McMahon, M. (2007) · Genes & Development · doi:10.1101/gad.1516407 · Cited by 492
Discovery of A Ca2+‐and calmodulin‐dependent protein phosphatase
Stewart, A. A., Ingebritsen, T. S., Manalan, A. S., Klee, C. B., & Cohen, P. (1982) · FEBS Letters · doi:10.1016/0014-5793(82)80319-0 · Cited by 483
Bivona, T. G., Quatela, S. E., Bodemann, B. O., Ahearn, I. M., Soskis, M. J., Mor, A., Miura, J., Wiener, H. H., Wright, L. P., Saba, S. G., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.012 · Cited by 467
Detection of Circulating Tumour DNA in the Blood (Plasma/Serum) of Cancer Patients
Anker, P., Mulcahy, H. E., Chen, X. Q., & Stroun, M. (1999) · Cancer and Metastasis Reviews · doi:10.1023/a:1006260319913 · Cited by 451
Balmain, A., & Pragnell, I. B. (1983) · Nature · doi:10.1038/303072a0 · Cited by 424
Self-citationK-Ras is essential for the development of the mouse embryo
Koera, K., Nakamura, K. D., Nakao, K., Miyoshi, J., Toyoshima, K., Hatta, T., Otani, H., Aiba, A., & Katsuki, M. (1997) · Oncogene · doi:10.1038/sj.onc.1201284 · Cited by 355
SnapShot: Noncanonical Wnt Signaling Pathways
Semënov, M. V., Habas, R., MacDonald, B. T., & He, X. (2007) · Cell · doi:10.1016/j.cell.2007.12.011 · Cited by 349
Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor
Antal, C. E., Hudson, A., Kang, E., Zanca, C., Wirth, C., Stephenson, N. L., Trotter, E. W., Gallegos, L. L., Miller, C. J., Furnari, F. B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.001 · Cited by 331
The Wnt/calcium pathway activates NF-AT and promotes ventral cell fate in Xenopus embryos
Saneyoshi, T., Kume, S., Amasaki, Y., & Mikoshiba, K. (2002) · Nature · doi:10.1038/417295a · Cited by 322 · cited 2×
“The non-canonical Wnt/Ca2+ pathway involves activation of CaMKii and the transcription factor NF-AT and inhibition of b-catenin/TCF signaling (Saneyoshi et al., 2002; Semenov et al., 2007; Sugimura and Li, 2010).”
BackgroundThe Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations
Page, M. E., Lombard, P., Ng, F., Göttgens, B., & Jensen, K. B. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.07.010 · Cited by 320
Noncanonical Wnt Signaling Maintains Hematopoietic Stem Cells in the Niche
Sugimura, R., He, X., Venkatraman, A., Arai, F., Box, A., Semerad, C. L., Haug, J. S., Peng, L., Zhong, X.-B., Suda, T., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.041 · Cited by 306
Functional Specificity of Ras Isoforms: So Similar but So Different
Castellano, E., & Santos, E. (2011) · Genes & Cancer · doi:10.1177/1947601911408081 · Cited by 290
The multifunctional Ca2+/calmodulin-dependent protein kinases
Schulman, H. (1993) · Current Opinion in Cell Biology · doi:10.1016/0955-0674(93)90111-3 · Cited by 244
Differential Expression of the ras Gene Family in Mice
León, J., Guerrero, I., & Pellicer, À. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.4.1535 · Cited by 225
Herbst, A., Jurinović, V., Krebs, S., Thieme, S. E., Blum, H., Göke, B., & Kolligs, F. T. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-74 · Cited by 215
Expression of ras proto-oncogene proteins in normal human tissues.
Furth, M. E., Aldrich, T. H., & Cordon‐Cardo, C. (1987) · PubMed · Cited by 215
Tumor Promotion by Depleting Cells of Protein Kinase Cδ
Lu, Z., Hornia, A., Jiang, Y.-W., Zang, Q. S., Ohno, S., & Foster, D. A. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.6.3418 · Cited by 207
Calmodulin Binds to K-Ras, but Not to H- or N-Ras, and Modulates Its Downstream Signaling
Villalonga, P., López-Alcalá, C., Bosch, M., Chiloeches, A., Rocamora, N., Gil, J., Marais, R., Marshall, C. J., Bachs, O., & Agell, N. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.21.7345-7354.2001 · Cited by 181
Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases
Sugimura, R., & Li, L. (2010) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20195 · Cited by 174
Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines
Honoki (2009) · International Journal of Oncology · doi:10.3892/ijo_00000265 · Cited by 166
The hair follicle—a stem cell zoo
Jaks, V., Kasper, M., & Toftgård, R. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.03.014 · Cited by 160
Chesa, P. G., Rettig, W. J., Melamed, M. R., Old, L. J., & Niman, H. L. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.10.3234 · Cited by 156
Two Faces of Protein Kinase Cδ: The Contrasting Roles of PKCδ in Cell Survival and Cell Death
Basu, A., & Pal, D. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.214 · Cited by 132
Gou, S., Liu, T., Wang, C., Yin, T., Li, K., Yang, M., & Zhou, J. (2007) · Pancreas · doi:10.1097/mpa.0b013e318033f9f4 · Cited by 130
Potenza, N., Vecchione, C., Notte, A., Rienzo, A. D., Rosica, A., Bauer, L., Affuso, A., Felice, M. D., Russo, T., Poulet, R., et al. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400397 · Cited by 126
Kras regulatory elements and exon 4A determine mutation specificity in lung cancer
To, M. D., Wong, C. E., Karnezis, A. N., Rosario, R. D., Lauro, R. D., & Balmain, A. (2008) · Nature Genetics · doi:10.1038/ng.211 · Cited by 117
Self-citationQuinlan, M. P., Quatela, S. E., Philips, M. R., & Settleman, J. E. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01661-07 · Cited by 96
Calmodulin and calmodulin-binding proteins in the nucleus
Bachs, O., Agell, N., & Carafoli, E. (1994) · Cell Calcium · doi:10.1016/0143-4160(94)90092-2 · Cited by 87
Szállási, Z., Krsmanović, L. Z., & Blumberg, P. M. (1993) · PubMed · Cited by 85
Cheng, C., Omura‐Minamisawa, M., Kang, Y. H., Hara, T., Koike, I., & Inoue, T. (2008) · Cancer Science · doi:10.1111/j.1349-7006.2008.01021.x · Cited by 80
Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation
Márquez, N., Calzado, M. A., Sánchez‐Duffhues, G., Pérez, M., Minassi, A., Pagani, A., Appendino, G., Díaz, L., Muñoz‐Fernández, M. Á., & Muñóz, E. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.12.004 · Cited by 80
López-Alcalá, C., Alvarez-Moya, B., Villalonga, P., Calvo, M., Bachs, O., & Agell, N. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706238200 · Cited by 71
Wong, C. E., Yu, J. S., Quigley, D. A., To, M. D., Jen, K., Huang, P., Rosario, R. D., & Balmain, A. (2013) · Genes & Development · doi:10.1101/gad.210427.112 · Cited by 62
Self-citationStructure Activity Relations of Polyfunctional Diterpenes of the Tigliane Type, VI1
Zayed, S., Sorg, B. L., & Hecker, E. (1984) · Planta Medica · doi:10.1055/s-2007-969623 · Cited by 47
Evaluation of cell-free DNA as a biomarker for pancreatic malignancies
Sikora, K. O., Bedin, C., Vicentini, C., Malpeli, G., D’Angelo, E., Sperandio, N., Lawlor, R. T., Bassi, C., Tortora, G., Nitti, D., et al. (2014) · The International Journal of Biological Markers · doi:10.5301/jbm.5000088 · Cited by 42
Molecular cloning and characterization of human Frizzled-8 gene on chromosome 10p11.2
Saitoh, T., Hirai, M., & Katoh, M. (2001) · International Journal of Oncology · doi:10.3892/ijo.18.5.991 · Cited by 41
Calmodulin-dependent protein kinase IV: regulation of function and expression
Krebs, J. (1998) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(98)00142-6 · Cited by 31
Feng, W., Liu, Y., Bellail, A. C., Olson, J. J., Sun, S. Y., Lu, G., Ding, L., Yuan, C., Wang, G., & Hao, C. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.02.005 · Cited by 28
The Many Faces of Wnt and Pancreatic Ductal Adenocarcinoma Oncogenesis
Weekes, C. D., & Winn, R. A. (2011) · Cancers · doi:10.3390/cancers3033676 · Cited by 10
(2003) · PubMed
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RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
Self-citationDirect small-molecule inhibitors of KRAS: from structural insights to mechanism-based design
Ostrem, J. M. L., & Shokat, K. M. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.139 · Cited by 641
The calcium–cancer signalling nexus
Monteith, G. R., Prevarskaya, N. B., & Roberts‐Thomson, S. J. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.18 · Cited by 649
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
Katoh, M. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.4129 · Cited by 478
Metadata
- 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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