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Review
. 2016 Nov 29;8(12):107.
doi: 10.3390/cancers8120107.

Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response

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Free PMC article
Review

Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response

Viralkumar Davra et al. Cancers (Basel). .
Free PMC article

Abstract

The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice.

Keywords: Axl; Gas6; Mertk; Tyro3; immune evasion; protein S; tumor microenvironment.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TAM receptor activation by Gas6, Pros1, and PS-positive apoptotic cells. TAM receptors exhibit differential activation by their ligands, Gas6 and Pros1. While Gas6 preferentially activates Axl and to lesser extent Tyro3 and Mertk; Pros1 does not activate Axl and is specific for Mertk and Tyro3. However, in the presence of externalized phosphatidylserine (PS) on the surface of apoptotic cells, stressed tumor vasculature, or PS- positive tumor exosomes, Gas6 and Pros1 mediated activation of TAMs is enhanced. After ligand binding, TAMs undergo subsequent dimerization and auto-phosphorylation of catalytic tyrosine kinase domain leading to downstream effector pathways.
Figure 2
Figure 2
Post-translational modifications of Gas6 by γ-glutamyl carboxylation. Gas6 can be transcriptionally upregulated by autocrine or paracrine mechanisms. Following translation, un-carboxylated Gas6 (inactive) is activated by a series of enzymatic steps involving γ-glutamyl carboxylation via the vitamin-K-dependent enzyme γ-glutamyl carboxylase (Ggcx). The carboxylated (active) Gas6 from ER is transported to the Golgi apparatus through trans-Golgi network and then into secretory vesicles. The Vit-K epoxide reductase enzyme complex 1 (Vkorc1) then completes the Vit-K cycle by recycling this epoxide back to hydroquinone, which in turn serves as a co-factor in the Ggcx induced γ-carboxylation of Gas6 and Pros1. Warfarin, which functions as a direct inhibitor Vkorc1 prevents γ-carboxylation of Gas6 and Pros1 and prevents TAM receptor activation in the tumor microenvironment.
Figure 3
Figure 3
The role of TAM receptors in the tumor microenvironment. Various types of cells including tumor cells, macrophages, DCs, T-cells and apoptotic cells in addition to stressed tumor vasculature and phosphatidylserine (PS) positive tumor exosomes contribute to the tumor vasculature. In the tumor microenvironment, Gas6 binds to PS on the apoptotic cells and tumor exosomes and activates TAM receptors (TAMs) on tumor cells as well as on phagocytes such as macrophages, and DCs (professional phagocytes). Activation of TAMs on the tumor cells drive tumor growth and metastasis via downstream effector signaling leading to tumor cell survival, proliferation, chemoresistance and EMT phenotypes. On the other hand, activation of TAMs on the professional phagocytes leads to engulfment of apoptotic cells (efferocytosis), which in turn drives immune evasion by inhibiting T-cell priming and activation as well as via inhibition of NF-κB and inflammatory cytokine production. Hence, TAMs may act as dual tumorigenic gene products, first by acting as direct drivers of tumor growth, and second by acting as inhibitory immune receptors in the tumor microenvironment.

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