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| The diagram on the top depicts the domain organization of the AXL receptor tyrosine kinase. The intracellular kinase domain includes the seven-residue sequence conserved among TAM family receptor tyrosine kinases: at positions 3 and 5 within this conserved sequence, AXL and MERTK contain isoleucine (I) residues, while TYRO3 contains leucine (L) residues. Proteolytic cleavage of residues between the transmembrane and closest FNIII domains renders a soluble isoform of AXL, which contains its fully functioning extracellular domains. The diagram on the bottom depicts the domain structure of GAS6, the AXL ligand. GAS6 is activated by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain. |
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Description | The full-length AXL protein contains 894 amino acids and has a molecular weight of 104 kDa. As the extracellular domain contains six N-linked glycosylation sites, two other post-translationally modified forms weighing 120 and 140 kDa -representing partial and complete glycosylation, respectively- have been identified. The extracellular component of the AXL receptor contains two Ig-like domains (aa 37-124 for domain 1, 141-212 for domain 2) followed by two FNIII domains (aa 224-322 for domain 1, 325-428 for domain 2) (O'Bryan et al., 1991). This particular tandem arrangement defines AXL as part of the TAM family of receptor tyrosine kinases (RTKs), which also includes TYRO3 and MERTK (Graham et al., 1994). All three TAM family proteins bind the ligand GAS6, a vitamin K-dependent protein structurally similar to Protein S (PROS1), which activates MERTK and TYRO3 but not AXL (Prasad et al., 2006). Like all TAM family members, each immunoglobulin domain of the AXL receptor provides a binding site for each of the two laminin G-like (LG) domains of GAS6, the only identified ligand for AXL as of yet (Sasaki et al., 2006). Carboxy-terminal to the second FNIII domain, fourteen amino acids (aa 438-451 in the longer variant) serve as a proteolytic cleavage site, yielding an 80 kD soluble form of AXL with only the extracellular domains of the full-length protein. As this cleavage site translates from exon 11, proteins from both transcript variants are subject to proteolysis. The intact ligand-binding domains in this soluble form highlight its potential role in signal transduction as an inhibitor of the membrane-bound receptor (O'Bryan et al., 1995). The intracellular tyrosine kinase domain of AXL contains the sequence KW(I/L)A(I/L)ES (aa 714-720), which is conserved among all TAM family RTKs. Within this signature motif, the third and fifth amino acids are isoleucine (I) in both AXL and MERTK, while leucine (L) occupies these positions in TYRO3 (Graham et al., 1994). Activation of the AXL receptor occurs within its intracellular domain and is characterized by the phosphorylation of tyrosine residues at sites that have yet to be defined. MERTK is the only TAM family member with validated tyrosine autophosphorylation sites; AXL also has three tyrosine residues -Y697, Y702, and Y703- conserved in sequence context within its kinase domain, but no evidence exists implicating their role in autophosphorylation (Ling et al., 1996). Numerous mass spectrometry analyses confirm that these and several other tyrosine residues are, in fact, phosphorylated (Hornbeck et al., 2004), and a recent study demonstrated that phosphorylation occurs at Y702 and Y703 upon GAS6 stimulation (Pao-Chun et al., 2009). However, neither of these sites has been shown to directly regulate or interact with the downstream effectors of AXL activation. Three other tyrosine residues within the AXL intracellular domain -Y779, Y821, and Y866- mediate binding of various substrates, suggesting that they may be more likely candidates for autophosphorylation sites. Y779 partially contributes to binding PI3K, while Y866 plays an integral role in binding PLC. Y821 has been shown to be a critical docking site for multiple substrates, including PI3K, PLC, GRB2, c-SRC, and LCK (Braunger et al., 1997). Despite this evidence, an in vivo study refuted the significance of Y821 in AXL autophosphorylation and activation, as mutants without Y821 display normal GAS6-stimulated tyrosine phosphorylation (Fridell et al., 1996). Along with conventional ligand-induced dimerization and autophosphorylation, AXL activation can also occur through ligand-independent pathways. AXL overexpression causes homophilic binding between its extracellular domains on neighboring cells and leads to increased phosphorylation of its intracellular domain (Bellosta et al., 1995). AXL also engages in cross-talk with the IL-15 receptor, which transactivates AXL and requires it for survival from TNF-alpha-mediated apoptosis (Budagian et al., 2005). |
Expression | AXL is expressed throughout all tissue and cell types (O'Bryan et al., 1991). Higher expression is observed in endothelial cells, heart and skeletal muscle, liver, kidney, testis, platelets, myelomonocytic cells, hippocampus, and cerebellum (Neubauer et al., 1994; Bellosta et al., 1995; Graham et al., 1995; Angelillo-Scherrer et al., 2001). Relative to normal expression levels, AXL is increased in a number of disease states as reviewed by Linger et al (2008). |
Localisation | AXL is a transmembrane receptor tyrosine kinase. |
Function | Activation of the AXL receptor initiates various signaling pathways involved in cell survival, proliferation, apoptosis inhibition, migration, cell adhesion, and cytokine production. This is mediated via interactions with a spectrum of signaling molecules, including PI3K/Akt, ERK1/ERK2, GRB2, RAS, RAF1, MEK-1, and SOCS-1. Beyond its overexpression and oncogenic potential in numerous cancers, AXL has also been implicated in angiogenesis and metastasis (Linger et al., 2008). |
Homology | AXL and the two other TAM family members, MERTK and TYRO3, share 31-36% and 54-59% sequence identities in the extracellular and intracellular regions, respectively (Graham et al., 1995). |
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