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

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.

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

“…RTKs include 20 families that are distinguished by amino acid sequence identity within the kinase domain and exhibit structural similarities within their extracellular regions [5]. This review focuses on the TAM family, which is one of the latest to evolve and last to be identified [2,6].…”

“…The TAM family includes three receptors, tyrosine kinase receptor 3 (Tyro3), Axl, and Mer, which share the vitamin K-dependent ligands, growth arrest-specific protein 6 (Gas6) and protein S. Gas6 binds all three TAM receptors, and protein S binds only Tyro3 and Mer [2,6]. The most prevalent functions of the TAM family and their ligands were investigated in tumour genesis [2,6].…”

“…The most prevalent functions of the TAM family and their ligands were investigated in tumour genesis [2,6]. Tyro3, Axl, and Mer are overexpressed in numerous cancers, including myeloid and lymphoblastic leukaemias, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancers [2,6].…”

“…Tyro3, Axl, and Mer are overexpressed in numerous cancers, including myeloid and lymphoblastic leukaemias, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancers [2,6]. TAM receptor induction in tumour cells predominately promotes survival, chemoresistance and motility [2,6]. Inhibition of TAM kinases stimulates antitumour immunity, reduces tumour cell survival, enhances chemosensitivity and diminishes metastatic potential [2,6].…”

Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma

“…Externalized PS is also a well-characterized cell marker that is primarily responsible for the recognition and uptake of dying apoptotic cells by phagocytes and for quelling potential autoimmune responses (28). Activation of phagocytic cells is mediated by the interaction of PS with the TAM (TYRO3, AXL, and MERTK) and TIM (T-cell immunoglobulin and mucin) families of PS receptors that induce expression of immune suppressive cytokines, dampen inflammatory signaling mechanisms, and inhibit innate immune cellular responses (29)(30)(31). Tumor vasculature-endothelial cells (32,33), tumor-derived microvesicles (34), and tumor cells all exhibit PS-mediated "apoptotic mimicry" to suppress proinflammatory antitumor immune responses (35)(36)(37).…”