The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells
Open accessAbstract
Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
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Immune cells can attenuate metastasis.
“On one hand, there is evidence that immune cells have the capability to attenuate metastasis[54–59], which provides insight into how to restore or enhance their ability to combat cancer.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [56]
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Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989 · see citing works
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · see citing works
Pulaski, B. A., & Ostrand‐Rosenberg, S. (2000) · Current Protocols in Immunology · doi:10.1002/0471142735.im2002s39 · Cited by 912 · see citing works
Immunobiology of the TAM receptors
Lemke, G., & Rothlin, C. V. (2008) · Nature reviews. Immunology · doi:10.1038/nri2303 · Cited by 867 · see citing works
Linger, R. M. A., Keating, A. K., Earp, H. S., & Graham, D. K. (2008) · Advances in cancer research · doi:10.1016/s0065-230x(08)00002-x · Cited by 750 · see citing works
Homeostatic Regulation of the Immune System by Receptor Tyrosine Kinases of the Tyro 3 Family
Lu, Q., & Lemke, G. (2001) · Science · doi:10.1126/science.1061663 · Cited by 699 · see citing works
Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b
Bachmaier, K., Krawczyk, C. M., Kozieradzki, I., Kong, Y., Sasaki, T., Oliveira-dos-Santos, A., Mariathasan, S., Bouchard, D., Wakeham, A. C., Itié, A., et al. (2000) · Nature · doi:10.1038/35003228 · Cited by 674 · see citing works
Self-citationThe Role of the NKG2D Immunoreceptor in Immune Cell Activation and Natural Killing
Jamieson, A. M., Diefenbach, A., McMahon, C. W., Xiong, N., Carlyle, J. R., & Raulet, D. H. (2002) · Immunity · doi:10.1016/s1074-7613(02)00333-3 · Cited by 647 · see citing works
Self-citationCerwenka, A., Baron, J. L., & Lanier, L. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201238598 · Cited by 606 · see citing works
Nagata, K., Ohashi, K., Nakano, T., Arita, H., Zong, C., Hanafusa, H., & Mizuno, K. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.30022 · Cited by 541 · see citing works
Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46
Walzer, T., Bléry, M., Chaix, J., Fuséri, N., Chasson, L., Robbins, S. H., Jaeger, S., André, P., Gauthier, L., Daniel, L., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609692104 · Cited by 476 · see citing works
Differential Effects of EGFR Ligands on Endocytic Sorting of the Receptor
Roepstorff, K., Grandal, M. V., Henriksen, L., Knudsen, S. L. J., Lerdrup, M., Grøvdal, L. M., Willumsen, B. M., & van Deurs, B. (2009) · Traffic · doi:10.1111/j.1600-0854.2009.00943.x · Cited by 344 · see citing works
Warfarin: almost 60 years old and still causing problems
Pirmohamed, M. (2006) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2006.02806.x · Cited by 337 · see citing works
An efficient proteomics method to identify the cellular targets of protein kinase inhibitors
Godl, K., Wissing, J. B., Kurtenbach, A., Habenberger, P., Blencke, S., Gutbrod, H., Salassidis, K., Stein-Gerlach, M., Missio, A., Cotten, M. L., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2535024100 · Cited by 337 · see citing works
The role of ubiquitylation in receptor endocytosis and endosomal sorting
Haglund, K., & Đikić, I. (2012) · Journal of Cell Science · doi:10.1242/jcs.091280 · Cited by 310 · see citing works
In vivo effect of anti-asialo GM1 antibody on natural killer activity
Kasai, M., Yoneda, T., Habu, S., MARUYAMA, Y., Okumura, K., & Tokunaga, T. (1981) · Nature · doi:10.1038/291334a0 · Cited by 272 · see citing works
Predominant expression of invariant Vα14+ TCR α chain in NK1.1+ T cell populations
Makino, Y., Kanno, R., Ito, T., Higashino, K., & Taniguchi, M. (1995) · International Immunology · doi:10.1093/intimm/7.7.1157 · Cited by 254 · see citing works
Immunotherapy of autoimmunity and cancer: the penalty for success
Caspi, R. R. (2008) · Nature reviews. Immunology · doi:10.1038/nri2438 · Cited by 182 · see citing works
Spontaneous tumor rejection by cbl-b –deficient CD8+ T cells
Loeser, S., Loser, K., Bijker, M. S., Rangachari, M., van der Burg, S. H., Wada, T., Beissert, S., Melief, C. J. M., & Penninger, J. M. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061699 · Cited by 161 · see citing works
Self-citationNatural killer cell differentiation driven by Tyro3 receptor tyrosine kinases
Caraux, A., Lu, Q., Fernandez, N. C., Riou, S., Santo, J. P. D., Raulet, D. H., Lemke, G., & Roth, C. (2006) · Nature Immunology · doi:10.1038/ni1353 · Cited by 157 · see citing works
Molecular and Genetic Basis for Strain-Dependent NK1.1 Alloreactivity of Mouse NK Cells
Carlyle, J. R., Mesci, A., Ljutic, B., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.12.7511 · Cited by 144 · see citing works
Ablation of Cbl-b provides protection against transplanted and spontaneous tumors
Chiang, J. Y., Jang, I. K., Hodes, R., & Gu, H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29472 · Cited by 124 · see citing works
A study of the mechanism by which anticoagulation with warfarin inhibits blood-borne metastases.
Jm, B. (1973) · PubMed · Cited by 120 · see citing works
Gas6 Regulates Mesangial Cell Proliferation through Axl in Experimental Glomerulonephritis
Yanagita, M., Arai, H., Ishii, K., et al. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64093-x · Cited by 113 · see citing works
Brehmer, D., Godl, K., Zech, B., Wissing, J. B., & Daub, H. (2004) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m300139-mcp200 · Cited by 108 · see citing works
Lee-MacAry, A. E., Ross, E. L., Davies, D. C., et al. (2001) · Journal of Immunological Methods · doi:10.1016/s0022-1759(01)00336-2 · Cited by 107 · see citing works
Nagai, K., Arai, H., Yanagita, M., Matsubara, T., Kanamori, H., Nakano, T., Iehara, N., Fukatsu, A., Kita, T., & Doi, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213266200 · Cited by 105 · see citing works
Essential Role of E3 Ubiquitin Ligase Activity in Cbl-b–Regulated T Cell Functions
Paolino, M., Thien, C. B. F., Gruber, T., Hinterleitner, R., Baier, G., Langdon, W. Y., & Penninger, J. M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003390 · Cited by 98 · see citing works
Self-citationThe role of γ-carboxylation in the anti-apoptotic function of gas6
Hasanbasic, I., Rajotte, I., & Blostein, M. D. (2005) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2005.01662.x · Cited by 98 · see citing works
Roadblocks to translational advances on metastasis research
Brabletz, T., Lyden, D. C., Steeg, P. S., & Werb, Z. (2013) · Nature Medicine · doi:10.1038/nm.3327 · Cited by 88 · see citing works
Harshan, K. V., & Gangadharam, P. R. (1991) · Infection and Immunity · doi:10.1128/iai.59.8.2818-2821.1991 · Cited by 87 · see citing works
Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1
Kojo, S., Elly, C., Harada, Y., Langdon, W. Y., Kronenberg, M., & Liu, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904078106 · Cited by 77 · see citing works
Self-citationEffects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation
Valverde, P. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.086 · Cited by 74 · see citing works
Reduced Incidence of Spontaneous Metastases with Long-Term Coumadin* Therapy
Ryan, J. J., Ketcham, A. S., & Wexler, H. (1968) · Annals of Surgery · doi:10.1097/00000658-196807000-00021 · Cited by 51 · see citing works
Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth
McCulloch, P. G., & George, W. (1989) · British Journal of Cancer · doi:10.1038/bjc.1989.37 · Cited by 50 · see citing works
Immunobiology of Her-2/Neu Transgenic Mice
Pannellini, T., Forni, G., & Musiani, P. (2004) · Breast Disease · doi:10.3233/bd-2004-20105 · Cited by 43 · see citing works
Oksvold, M. P., Dagger, S. A., Thien, C. B. F., & Langdon, W. Y. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2007.08.002 · Cited by 26 · see citing works
Self-citationLacour, F., OBERLING, C., & GUERIN, M. (2000) · PubMed · Cited by 4 · see citing works
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Metastatic colonization by circulating tumour cells
Massagué, J., & Obenauf, A. C. (2016) · Nature · doi:10.1038/nature17038 · Cited by 2,062 · see citing works
Immune cell promotion of metastasis
Kitamura, T., Qian, B.-Z., & Pollard, J. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3789 · Cited by 1,158 · see citing works
Kinase inhibitors: the road ahead
Ferguson, F. M., & Gray, N. S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.21 · Cited by 1,009 · see citing works
Principles of Ubiquitin-Dependent Signaling
Oh, E., Akopian, D., & Rape, M. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062802 · Cited by 339 · see citing works
Microfluidics: A New Tool for Modeling Cancer–Immune Interactions
Boussommier-Calleja, A., Li, R., Chen, M. B., Wong, S. C., & Kamm, R. D. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2015.12.003 · Cited by 224 · see citing works
Miner, J. J., Daniels, B. P., Shrestha, B., Proenca-Modena, J. L., Lew, E. D., Lazear, H. M., Gorman, M. J., Lemke, G., Klein, R. S., & Diamond, M. S. (2015) · Nature Medicine · doi:10.1038/nm.3974 · Cited by 152 · see citing works
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Wirnsberger, G., Zwolanek, F., Asaoka, T., Kozieradzki, I., Tortola, L., Wimmer, R. A., Kavirayani, A., Fresser, F., Baier, G., Langdon, W. Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4134 · Cited by 113 · see citing works
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Tortola, L., Nitsch, R., Bertrand, M. J. M., Kogler, M., Redouane, Y., Kozieradzki, I., Uribesalgo, I., Fennell, L. M., Daugaard, M., Klug, H., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.032 · Cited by 64 · see citing works
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Werneth, C. M., Slaba, T. C., Huff, J. L., Patel, Z. S., & Simonsen, L. C. (2022) · Health Physics · doi:10.1097/hp.0000000000001572 · Cited by 13 · see citing works
- Authors
- Paolino, M., Choidas, A., Wallner, S., Pranjic, B., Uribesalgo, I., Loeser, S., Jamieson, A. M., Langdon, W. Y., Ikeda, F., Fededa, J. P., Cronin, S. J., Nitsch, R., Schultz-Fademrecht, C., Eickhoff, J., Menninger, S., Unger, A., Torka, R., Gruber, T., Hinterleitner, R., Baier, G., Wolf, D., Ullrich, A., Klebl, B. M., & Penninger, J. M.
- Affiliations
- Institute of Molecular Biotechnology (AT)
- Lead Discovery Center (Germany) (DE)
- Innsbruck Medical University (AT)
- Brown University (US)
- The University of Western Australia (AU)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Penninger, Josef M.
- ORCID
- Venue
- Nature
- Published
- 2014-02-19
- Volume
- 507
- Issue
- 7493
- Pages
- 508-512
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6258903
- OpenAlex
- W2088565779
- Cited by
- 456
- References
- 38
- Citations by year
- 2026: 13 · 2025: 35 · 2024: 31 · 2023: 43 · 2022: 29 · 2021: 44 · 2020: 47 · 2019: 40 · 2018: 39 · 2017: 44 · 2016: 45 · 2015: 22 · 2014: 23
- FWCI
- 20.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Funders
- Österreichischen Akademie der Wissenschaften
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- Cbl-b, E3 ubiquitin ligase, TAM receptors, natural killer cells, metastasis, Tyro3, AXL, Mer, MERTK, warfarin, anti-metastatic therapy, melanoma metastasis, innate immunity
- MeSH terms
- c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Animals, Anticoagulants, Female, Killer Cells, Natural, Male, Mammary Neoplasms, Experimental, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, Proto-Oncogene Proteins, Warfarin, Receptor Protein-Tyrosine Kinases, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-cbl, Mice, Ubiquitination
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