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 down-stream 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 over-expressed 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.

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

“…AXL and its ligand, growth arrest-specific 6 are implicated in the pathogenesis of several human cancers including breast, lung, ovarian and prostate cancers and glioblastomas (Zhang et al, 2008;Shieh et al, 2005;Rankin et al, 2010;Sainaghi et al, 2005;Hutterer et al, 2008). AXL/growth arrest-specific 6 binding results in receptor dimerisation, tyrosine phosphorylation and activation of downstream pathways that regulate cytoskeletal dynamics/cell motility, cell survival and proliferation (reviewed in Linger et al, 2008). In addition, there is a structural basis for ligand-independent activation of AXL via homophilic cell adhesion (Heiring et al, 2004).…”

“…This protein was selected for further studies for several reasons. First, AXL is an oncogene implicated in cell motility, adhesion and cell growth (Linger et al, 2008), suggesting that it may function in the same pathways as Fra-1. Second, we observed a perfect correlation between Fra-1 and AXL expression in bladder cancer cells.…”

Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme

“…The ligands of Tyro3, Axl and Mer receptors are protein S and growth arrest-specific gene 6 (Gas6). 8 As MerTK has a low-binding affinity for these ligands, other unknown ligand(s) or conditions may be required for MerTK activation. 9 Full activation of MerTK requires the autophosphorylation of tyrosine residues 749, 753 and 754 within the kinase domain.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…This process is particularly increased under hypoxia since HIF-1α and HIF-2α have been demonstrated to bind to a functional HIF binding site in the AXL promoter, leading to increased expression of AXL in ccRCC cells [62]. AXL has been described as an important mediator of tumor invasion and metastasis in a number of cancers [64]. Of therapeutic relevance, the invasive and metastatic phenotype of ccRCC cells in particular, has been reported to reverse by inactivation of the GAS6/AXL signalling axis using a soluble AXL decoy receptor [62].…”