TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer

Abstract

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and downstream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are overexpressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

Fig. 1

Structure, binding, and activation of TAM receptors are their ligands. (A) Domain organization of Tyro-3, Axl, and Mer. The conserved sequence within the kinase domain is indicated. (B) Domain structure of the TAM receptor ligands, Gas6 and Protein S. Protein S contains thrombin cleavage sites in the loop region and has not been shown to activate Axl. (C) Axl binds to Gas6 with 2:2 stoichiometry as shown from the side (i) and from the top (ii). No ligand/ligand or receptor/receptor contacts were observed in crystals of the minimal complex containing the two LG domains of Gas6 and the two Ig domains of Axl. (D) Possible means of TAM receptor activation include: (i) ligand-independent dimerization, (ii) ligand-dependent dimerization, (iii) heteromeric dimerization of two different TAM receptors, (iv) heterotypic dimerization with a non-TAM receptor, and (v) trans-cellular binding of extracellular domains

Fig. 2

Mer signaling pathways lead to platelet aggregation, cell survival, regulation of proinflammatory cytokine production, and regulation of the actin cytoskeleton. Molecules in blue have been shown to associate with Mer through either a direct or indirect interaction. Tyrosines 749, 753, and 754 (yellow circles) within the Mer kinase domain are most likely sites of autophosphorylation. Vav1 binds to the region of Mer containing these phosphorylation sites (AA 697–754). It remains undetermined whether the interaction with Mer is direct or mediated by additional adapter proteins. Coimmunoprecipitation experiments suggest that several signaling molecules associate with phosphorylated tyrosine 872 of Mer via their SH2 domains. The kinase(s) which phosphorylate Mer at tyrosine 872 remain unknown. See text for full details. Amino acid designations are from the human sequences. Ub = ubiquitin.

Fig. 3

Axl signaling pathways lead to platelet aggregation, cell survival, proliferation, regulation of proinflammatory cytokine production, and regulation of the actin cytoskeleton. Molecules in blue have been shown to associate with Axl through either a direct or indirect interaction. Tyrosines 779, 821, and 866 of Axl are phosphorylated (yellow circles) and mediate interactions with a number of signaling molecules. It remains unknown whether these residues are sites of autophosphorylation or whether they are substrates for another protein tyrosine kinase. See text for full details. Amino acid designations are from the human sequences.

Fig. 4

Tyro-3 signaling pathways mediate platelet aggregation, cell transformation, and osteoclastic bone resorption. Molecules in blue have been shown to associate with Tyro-3 through either a direct or indirect interaction. Phosphorylation of Tyro-3 at specific residues remains uncharacterized.