TAM Signaling in the Nervous System
Open accessAbstract
Tyro3, Axl and Mertk are members of the TAM family of tyrosine kinase receptors. TAMs are activated by two structurally homologous ligands GAS6 and PROS1 . TAM receptors and ligands are widely distributed and often co-expressed in the same cells allowing diverse functions across many systems including the immune , reproductive, vascular, and the developing as well as adult nervous systems . This review will focus specifically on TAM signaling in the nervous system, highlighting the essential roles this pathway fulfills in maintaining cell survival and homeostasis , cellular functions such as phagocytosis , immunity and tissue repair. Dysfunctional TAM signaling can cause complications in development, disruptions in homeostasis which can rouse autoimmunity, neuroinflammation and neurodegeneration . The development of therapeutics modulating TAM activities in the nervous system has great prospects, however, foremost we need a complete understanding of TAM signaling pathways.
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PROS1 acts as an anti-inflammatory mediator by activating TAM (TYRO3, AXL, and MERTK) receptors, facilitating the phagocytic clearance of apoptotic cells and dampening inflammation.
“PROS1 acts as an anti‐inflammatory mediator by activating TAM (TYRO3, AXL, and MERTK) receptors, facilitating the phagocytic clearance of apoptotic cells and dampening inflammation. 48”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [48]
The neuroimmune-interface section says PROS1 helps bridge apoptotic cells to phagocytes, promoting their clearance and anti-inflammatory signaling. But the receptors-and-ligands section explicitly says PROS1 activates TYRO3 and MERTK, not AXL; the claim incorrectly includes AXL among the receptors PROS1 activates. No page number is available in our copy. (LLM, conf=0.92)
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Protein S drives oral squamous cell carcinoma tumorigenicity through regulation of AXL
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Self-citationSainaghi, P. P., Collimedaglia, L., Alciato, F., Molinari, R., Sola, D., Ranza, E., Naldi, P., Monaco, F., Leone, M. A., Pirisi, M., et al. (2013) · Mediators of Inflammation · doi:10.1155/2013/406483 · Cited by 47 · see citing works
PROTEIN S DEFICIENCY AND ANTIBODIES TO PROTEIN S IN PATIENTS WITH BEHCET'S DISEASE
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Gas6 Inhibits Toll-Like Receptor-Mediated Inflammatory Pathways in Mouse Microglia via Axl and Mer
Gilchrist, S. E., Goudarzi, S., & Hafizi, S. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.576650 · Cited by 44 · see citing works
Protein S Regulates Neural Stem Cell Quiescence and Neurogenesis
Zelentsova, K., Talmi, Z., Abboud-Jarrous, G., Sapir, T., Capucha, T., Nassar, M., & Burstyn‐Cohen, T. (2016) · Stem Cells · doi:10.1002/stem.2522 · Cited by 43 · see citing works
Self-citationHerrera-Rivero, M., Santarelli, F., Brosseron, F., Kummer, M. P., & Heneka, M. T. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1540-3 · Cited by 42 · see citing works
Zheng, Y., Wang, Q., Xiao, B., Lu, Q., Wang, Y., & Wang, X. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039035 · Cited by 40 · see citing works
Lumbroso, D., Soboh, S., Maimon, A., Schif‐Zuck, S., Ariel, A., & Burstyn‐Cohen, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.412281 · Cited by 40 · see citing works
Self-citationThe TAM receptor Tyro3 regulates myelination in the central nervous system
Akkermann, R., Aprico, A., Perera, A. A., Bujalka, H., Cole, A., Xiao, J., Field, J., Kilpatrick, T. J., & Binder, M. D. (2017) · Glia · doi:10.1002/glia.23113 · Cited by 38 · see citing works
Systemic Autoimmunity in TAM Triple Knockout Mice Causes Inflammatory Brain Damage and Cell Death
Li, Q., Lu, Q., Lü, H., Tian, S., & Lu, Q. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064812 · Cited by 38 · see citing works
Guermazi, S., Regnault, V., Gorgi, Y. L., Ayed, K., Lecompte, T., & Dellagi, K. (2000) · Blood Coagulation & Fibrinolysis · doi:10.1097/00001721-200007000-00012 · Cited by 38 · see citing works
TAM receptor signaling in development
Burstyn‐Cohen, T. (2017) · The International Journal of Developmental Biology · doi:10.1387/ijdb.160285tb · Cited by 34 · see citing works
Self-citationFunctional Consequences ofAXLSequence Variants in Hypogonadotropic Hypogonadism
Salian‐Mehta, S., Xu, M., Knox, A. J., Plummer, L., Slavov, D. B., Taylor, M. R. G., Bevers, S. G., Hodges, R. S., Crowley, W. F., & Wierman, M. E. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3426 · Cited by 33 · see citing works
Transcriptome Analysis of Neural Progenitor Cells by a Genetic Dual Reporter Strategy
Wang, J., Zhang, H., Young, A. G., Qiu, R., Herculian, S., Li, X., Wu, X., Lemke, G., & Lü, Q. (2011) · Stem Cells · doi:10.1002/stem.699 · Cited by 32 · see citing works
The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system
Blades, F., Aprico, A., Akkermann, R., Ellis, S. L., Binder, M. D., & Kilpatrick, T. J. (2018) · Glia · doi:10.1002/glia.23481 · Cited by 26 · see citing works
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Physiological Interactions between Microglia and Neural Stem Cells in the Adult Subependymal Niche
Sirerol-Piquer, M. S., Belenguer, G., Morante‐Redolat, J. M., Duart-Abadía, P., Pérez‐Villalba, A., & Fariñas, I. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.01.009 · Cited by 22 · see citing works
Protein S Negatively Regulates Neural Stem Cell Self-Renewal through Bmi-1 Signaling
Zelentsova, K., Talmi, Z., Abboud-Jarrous, G., Capucha, T., Sapir, T., & Burstyn‐Cohen, T. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00124 · Cited by 21 · see citing works
Self-citationNGF-induced Tyro3 and Axl function as survival factors for differentiating PC12 cells
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Cell-intrinsic regulation of murine epidermal Langerhans cells by protein S
Tabib, Y., Jaber, N. S., Nassar, M., Capucha, T., Mizraji, G., Nir, T., Koren, N., Aizenbud, I., Maimon, A., Eli‐Berchoer, L., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800303115 · Cited by 16 · see citing works
Self-citationAssociation of plasma levels of Protein S with disease severity in multiple sclerosis
Gerry, Z. M., Giuffrida, L., Gresle, M. M., Haartsen, J., Laverick, L., Butzkueven, H., Field, J., Binder, M. D., & Kilpatrick, T. J. (2015) · Multiple Sclerosis Journal - Experimental Translational and Clinical · doi:10.1177/2055217315596532 · Cited by 12 · see citing works
Blades, F., Wong, V. H. Y., Nguyen, C. T. O., Bui, B. V., Kilpatrick, T. J., & Binder, M. D. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00840 · Cited by 10 · see citing works
TAM receptors: two pathways to regulate adult neurogenesis
Ji, R., & Johnson, K. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.153671 · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
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Maitra, M., Mitsuhashi, H., Rahimian, R., Chawla, A., Yang, J., Fiori, L. M., Davoli, M. A., Perlman, K., Aouabed, Z., Mash, D. C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38530-5 · Cited by 164 · see citing works
TAM family kinases as therapeutic targets at the interface of cancer and immunity
DeRyckere, D., Huelse, J. M., Earp, H. S., & Graham, D. K. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00813-7 · Cited by 98 · see citing works
Therapeutic targeting of the functionally elusive TAM receptor family
Miao, Y. R., Rankin, E. B., & Giaccia, A. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00846-8 · Cited by 84 · see citing works
Prabhakar, N. K., Khan, H., Grewal, A. K., & Singh, T. G. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108902 · Cited by 58 · see citing works
TAM receptors in phagocytosis: Beyond the mere internalization of particles
Burstyn‐Cohen, T., & Fresia, R. (2023) · Immunological Reviews · doi:10.1111/imr.13267 · Cited by 58 · see citing works
Self-citationGas6/AXL pathway: immunological landscape and therapeutic potential
Zhai, X., Pu, D., Wang, R.-L., Zhang, J., Lin, Y., Wang, Y., Zhai, N., Peng, X., Zhou, Q., & Li, L. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1121130 · Cited by 43 · see citing works
Corticosterone effects induced by stress and immunity and inflammation: mechanisms of communication
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Synaptic pruning by microglia: lessons from genetic studies in mice
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Spatiotemporal dynamics of the cardioimmune niche during lesion repair
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Receptor tyrosine kinases (RTKs)
Batool, Z., Azfal, A., Liaquat, L., Sadir, S., Nisar, R., Inamullah, A., Ghalib, A. U. F., & Haider, S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-18677-6.00012-9 · Cited by 17 · see citing works
Siddique, I. A., Kamble, K., Gupta, S., Solanki, K., Bhola, S., Ahsan, N., & Gupta, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310499 · Cited by 16 · see citing works
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Zhang, Y.-Q., Yao, X., Zhu, H.-M., Lu, W., Malhi, K. K., Saleem, M. A. U., Li, X., & Li, J. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c01732 · Cited by 8 · see citing works
Prospects of current AXL-targeting therapies in early phase cancer trials
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Spatio-temporal dynamics of the fibrotic niche in cardiac repairPreprint
Chan, A., Greiner, J., Brennan, T. A., Agrawal, A., Hemmer, H., Sinning, K., Marschhäuser, L., Cheung, W. L., Iqbal, Z., Klesen, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.10.622609 · Cited by 7 · see citing works
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Vitamin K and the Visual System—A Narrative Review
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Macrophage-mediated refinement of the dural lymphatic regulates social behavior
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Structural basis of phosphatidylserine enhancement of Gas6 ligand-induced Axl activationPreprint
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- Authors
- Burstyn-Cohen, T., & Hochberg, A.
- Affiliations
- The Hebrew University-Hadassah
- Hebrew University of Jerusalem (IL)
- Venue
- Brain Plasticity
- Publisher
- IOS Press
- Published
- 2021-06
- Volume
- 7
- Issue
- 1
- Pages
- 33-46
- ISSN
- 2213-6304 (ISSN-L)
- 2213-6312
- PMC
- PMC8461745
- OpenAlex
- W3161391066
- Cited by
- 29
- References
- 117
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 2 · 2023: 9 · 2022: 4 · 2021: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- Brain Plasticity (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation (655/18)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- TAM receptors, Tyro3, AXL, MERTK, Gas6, protein S, nervous system, brain development, neuroinflammation, neurodegeneration, autoimmunity, phagocytosis, tissue repair, cell survival
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