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1.
Figure 4

Figure 4. Opportunities for therapeutic disruption of Mer and Axl signaling in the tumor microenvironment. From: Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

Axl and Mer expressed by tumor cells may be stimulated by autocrine or paracrine activation loops as the ligands Gas6 and Protein S are expressed by tumor cells and found in plasma. Gas6 is also released by infiltrating immune cells such as tumor-associated macrophages and dendritic cells. Blockade of Axl and Mer expressed by endothelial cells may inhibit angiogenesis.

Rachel M.A. Linger, et al. Expert Opin Ther Targets. ;14(10):1073-1090.
2.
Figure 3

Figure 3. Molecular strategies for therapeutic inhibition of receptor tyrosine kinases (RTKs). From: Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

(A) Low molecular weight tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate (ATP) for binding to the activation loop of the RTK. (B–D) Anti-RTK monoclonal antibodies can prevent binding of ligand (B) and/or cause endocytosis of the RTK (C) which may result in RTK degradation (D). (E) Ligand sequestration via anti-ligand monoclonal antibodies or recombinant fusion proteins such as the extracellular RTK domain fused to the Fc region of human IgG.

Rachel M.A. Linger, et al. Expert Opin Ther Targets. ;14(10):1073-1090.
3.
Figure 1

Figure 1. Axl and Mer receptor tyrosine kinases are similar but distinct. From: Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

Growth arrest specific gene 6 (Gas6) activates both receptors. Protein S (ProS), a well known anticoagulation factor, activates Mer but not Axl. The domain structure of Axl and Mer is identical, consisting of two immunoglobulin (Ig)-Like domains, two fibronectin type III (FNIII) domains, a single transmembrane domain, and an intracellular kinase domain. The intracellular regions of Axl and Mer contain 17 and 16 tyrosine residues, respectively. Thirteen of them are identical and six of those are symbolized here by a circled Y with the residue number indicated. Residues 698, 702, and 703 of Axl (749, 753, and 754 of Mer) lie within the activation loop. Yellow circles represent tyrosines which have been shown to be phosphorylated while phosphorylation of green tyrosines has not yet been demonstrated [118–122]. Percent amino acid homology within each domain as well as between the full-length proteins was determined using the Basic Local Alignment Search Tool (BLASTP 2.2.23+) to align the sequences of Axl (NP_068713.2) and Mer (NP_006334.2). The conserved sequence (KWIAIES) within the kinase domain distinguishes TAM receptors from other receptor tyrosine kinase families.

Rachel M.A. Linger, et al. Expert Opin Ther Targets. ;14(10):1073-1090.
4.
Figure 2

Figure 2. Axl and Mer signaling pathways in cancer cells. From: Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

Pathways activated downstream of both Mer and Axl, such as the Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (Akt) and Mitogen-activated protein kinase (MEK)/Extracellular-signal-regulated kinase (ERK) survival and proliferation pathways, are shown in purple. Blue pathways, including regulation of mammalian target of rapamycin (mTOR) [10], have been described downstream of Mer. Pathways downstream of Axl such as inactivation of Bcl-2-associated death promoter (BAD) via phosphorylation by Akt are shown in red. Mer interacts with, but does not directly phosphorylate, activated cdc42-associated kinase 1 (Ack1). Activation of Ack1 may occur indirectly through the guanine nucleotide-exchange factor Vav1 and cdc42, resulting in degradation of the tumor suppressor protein WW domain containing oxidoreductase (Wwox) and regulation of cell migration [123]. Interestingly, Ack1 also interacts with Axl via Grb2 and may regulate Axl turnover or cleavage [122]. Gas6 stimulates Ack1-dependent phosphorylation of androgen receptor (AR) resulting in proliferation of prostate cancer cells in vitro, presumably via transcriptional regulation of androgen responsive genes [124]. This effect could be mediated by Mer and/or Axl since the cell types evaluated express both receptors. Axl expression is only found in estrogen receptor (ER)-positive patient samples, and ER antagonists reduce Axl expression in breast cancer cells [33, 72]. It has not been determined whether ER binds to the Axl promoter, but Gas6 expression is transcriptionally regulated by ER [75]. See text for explanation of other depicted pathways. Additional signaling pathways have been delineated in non-cancerous cells (reviewed in [17]). Hsp90β, heat shock protein 90β; IκB, inhibitor of kappa-B; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A.

Rachel M.A. Linger, et al. Expert Opin Ther Targets. ;14(10):1073-1090.

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