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The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer

Key Points

  • TYRO3, AXL and MERTK (TAM) rely on a unique mode of receptor tyrosine kinase (RTK) regulation — which involves a protein ligand and a lipid (phosphatidylserine) complex that binds to the extracellular domain — to trigger dimerization and kinase activation.

  • MERTK initiates efferocytosis in macrophages and epithelial cells, which has a crucial role in the efficient clearance of apoptotic material.

  • MERTK and AXL function in innate immune cells to suppress inflammatory responses.

  • Genetic deletion of Mertk in mice leads to autoimmunity, and additional deletion of Axl and Tyro3 increases the autoimmune, inflammatory response.

  • TAM RTKs carry out their physiological innate immune functions within tumours and thereby promote an immunosuppressive tumour microenvironment.

  • TAM RTKs and their ligands are overexpressed in neoplastic cells. Autocrine and paracrine stimulation of aberrantly expressed TAM RTKs provide intrinsic survival signals and promote resistance to molecularly targeted and cytotoxic therapies.

  • AXL has normal roles in vasculogenesis and in the migration of cells during development; AXL expression correlates with metastasis, epithelial-to-mesenchymal transition and motility in tumours.

  • TAM RTKs represent a dual target in neoplastic disease given their intrinsic roles in tumour cell survival and chemoresistance, and their immunosuppressive roles in the tumour microenvironment.

Abstract

The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.

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Figure 1: Schematic representation of the TAM family receptors.
Figure 2: Ligand-mediated activation of the TAM receptors.
Figure 3: Mechanisms of immunosuppression mediated by TAM RTKs in innate immune cells.
Figure 4: Signalling by TAM family RTKs.

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Acknowledgements

The authors thank A. Holtzhausen for her contribution to figure 2 and for her critical reading of the manuscript; S. Sather for her analysis of mutations in TAM family kinases; and S. Frye for helpful conversations. This work was supported by grants from the US National Cancer Institute (NCI) (to D.K.G. and H.S.E.), from the UNC Breast Cancer SPORE (to H.S.E.) and from the Breast Cancer Research Foundation (to H.S.E.).

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Correspondence to H. Shelton Earp.

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D.K.G. and H.S.E. are co-founders of Meryx, Inc., a company developing small-molecule MERTK kinase inhibitors. D.D. holds stock in Meryx, Inc.

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Glossary

M2-polarized macrophage

An alternatively activated macrophage that secretes immunosuppressive cytokines and growth factors to promote tissue repair.

Efferocytosis

The process by which macrophages and epithelial cells ingest apoptotic material.

Retinitis pigmentosa

An inflammatory process that occurs in the lining of the retina of the eye.

Involution

The process that occurs after lactation ceases, which results in substantial cell death in the milk-producing epithelium of the mammary gland.

Podocytes

Epithelial cells that wrap around the capillaries in the glomeruli of the kidney.

Sertoli cells

The cells in the male gonad that nourish the sperm-producing processes.

M1 macrophage

A macrophage that is activated by cytokines, or that is in contact with or has ingested foreign material, resulting in release of cytokines that initiate or prolong an inflammatory innate immune response.

Lipopolysaccharide

(LPS). A bacterial product that is sensed by specific Toll-like receptors on innate immune cells, which triggers a robust inflammatory response.

Chordates

Animals that have a notochord, a dorsal nerve chord and gill slits at one or more stages of development. This includes the vertebrates.

Non-oncogene addiction

Increased dependence of the neoplastic cell on the induction of endogenous cellular survival factors needed to prevent apoptosis in response to the hyperproliferative and altered metabolic states driven by oncogene expression or tumour suppressor loss.

Tingible body macrophages

Macrophages in the lymph node germinal centres that help to maintain tolerance to 'self' antigens.

Postpartum breast cancer

Breast cancer diagnosed in women after delivery of offspring. For reasons that have not been elucidated, the prognosis of postpartum breast cancer is worse than that of breast cancer diagnosed during pregnancy, even though both groups of women are premenopausal.

Aptamer

A synthesized RNA that is made or selected to bind to a specific target (usually a protein) with high affinity to modulate its function.

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Graham, D., DeRyckere, D., Davies, K. et al. The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 14, 769–785 (2014). https://doi.org/10.1038/nrc3847

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