The principal ligands that lead to TAM activation are growth arrest specific factor 6 (GAS6) and protein S, both of which require vitamin-K dependent γ-carboxylation to achieve maximal activation
[3][4]. These ligands vary in their affinity for the different TAM receptors: GAS6 binds all TAM receptors, with the highest affinity for AXL, while protein S only binds MER and TYRO3. These ligands can also bind the lipid moiety of phosphatidylserine (PS) and can activate TAMs when exposed on apoptotic cells, aggregating platelets, exosomes or virus envelopes
[5][6][7]. It has also been shown that GAS6 activation of AXL is localized at regions with high GAS6 concentration, resulting in a diffusional influx of AXL and receptor aggregation and dimerization
[8]. Furthermore, GAS6 can mediate dimer formation of other TAM members (MER or TYRO3), which have a lower affinity for GAS6 binding, and more experiments are needed to determine if the receptors can also heterodimerize and how this affects their signaling
[9][10][11]. Many laboratory studies have shown that the GAS6/AXL axis promotes cell invasion, proliferation and survival, thus contributing to cancer progression and metastasis. Conversely, clinical studies have shown a correlation between GAS6 expression and patients’ survival in breast cancer, suggesting that GAS6 may not be essential in this context
[12][13]. In support of this, it was observed that
GAS6 is dispensable in a pre-clinical model of HER2
+ breast cancer for the formation of metastases
[14]. Interestingly, AXL can be activated in a ligand-independent manner in many pathological contexts. For example, its increased expression, or the presence of oxidative stress, can lead to AXL homodimerization and autophosphorylation
[15][16][17]. Furthermore, AXL has been shown to crosstalk and heterodimerize or cluster with other RTKs such as EGFR, HER2, HER3, MET, PDGFR and VEGFR-2 to promote downstream signaling
[14][18][19][20][21][22][23][24]. These partnerships serve to diversify the downstream signaling of these RTKs and confer advantages to cancer cells. Through such a mechanism, AXL can promote resistance to a variety of therapies, including chemotherapy and targeted therapies including inhibitors of its partners EGFR, HER2 and PDGF
[18][25][26][27][28][29][30][31].