Abstract
The TAM subfamily (Tyro3, Axl, MerTK) of receptor tyrosine kinases are implicated in several cancers, where they have been shown to support primary tumorigenesis as well as secondary resistance to cancer therapies. Relatively little is known about the oncogenic role of Tyro3, including its ligand selectivity and signalling in cancer cells. Tyro3 showed widespread protein and mRNA expression in a variety of human cancer cell lines. In SCC-25 head and neck cancer cells expressing both Tyro3 and Axl, Western blotting showed that both natural TAM ligands ProS1 and Gas6 rapidly stimulated Tyro3 and Erk kinase phosphorylation, with ProS1 eliciting a greater effect. In contrast, Gas6 was the sole stimulator of Axl and Akt kinase phosphorylation. In MGH-U3 bladder cancer cells, which express Tyro3 alone, ProS1 was again the stronger stimulator of Tyro3 and Erk stimulation but additionally stimulated Akt phosphorylation. Conditioned medium from ProS1-secreting 786-0 kidney cancer cells replicated the kinase activation effects of recombinant ProS1 in SCC-25 cells, with specificity confirmed by ProS1 ligand traps and warfarin. In addition, ProS1 protected cancer cells from acute apoptosis induced by staurosporine, as well as additionally, long-term serum starvation-induced apoptosis in MGH-U3 cells (Tyro3 only), which reflects its additional coupling to Akt signalling in these cells. In conclusion, we have shown that ProS1 is a tumour-derived functional ligand for Tyro3 that supports cancer cell survival. Furthermore, the ProS1-Tyro3 interaction is primarily coupled to Erk signalling although it displays signalling diversity dependent upon its representative expression as a TAM receptor in tumour cells.
Highlights
The TAM (Tyro3, Axl, MerTK) subfamily of transmembrane receptor tyrosine kinases (RTKs) has been shown to regulate normal physiological processes such as tissue homeostasis and innate immunity [1]
We have investigated the expression of Tyro3 in a variety of human cancer cell lines and revealed that the ligand selectivity of Tyro3 is a factor of TAM expression profile in cancer cells
In MTS assays, staurosporine (0.1 μM) was used to acutely dependent TAM ligand, we investigated the functional effect of ProS1 on cells undergoing apoptosis trigger apoptosis, and the effects of TAM ligands on this was measured over 20 h
Summary
The TAM (Tyro, Axl, MerTK) subfamily of transmembrane receptor tyrosine kinases (RTKs) has been shown to regulate normal physiological processes such as tissue homeostasis and innate immunity [1]. Dysregulation of TAM signalling has been associated with chronic inflammatory and autoimmune conditions [2,3,4]. TAM signalling has been implicated in cancers, where each TAM RTK has in different studies been shown to regulate cancer cell growth, survival, proliferation, differentiation, migration or invasion [1,5]. The TAMs are increasingly being implicated as mediators of chemoresistance to other targeted therapies such as anti-EGFR (epidermal growth factor receptor) agents [6]. The TAMs present as attractive new targets in therapies aimed at combating tumour growth and spread. The protein structures of TAM receptors are identifiable by two N-terminal immunoglobulin (Ig)-like domains and two fibronectin type III domains in the extracellular region, a single-pass
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