Disease relevance of Axl

• The Gas6/Axl system is implicated in several types of human cancer as well as inflammatory, autoimmune, vascular and kidney diseases [1].
• Furthermore, Axl is expressed at high levels in human malignant glioma [2].
• We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis [3].
• Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy [3].
• The homology within the Axl family is highest between c-mer and c-eyk, the chicken proto-oncogene of the tumor virus gene product v-eyk [4].

High impact information on Axl

• We have generated and analysed null mutations in the mouse genes encoding three structurally related receptors with tyrosine kinase activity: Tyro 3, Axl, and Mer [5].
• This is also seen in mouse embryonic fibroblasts from wild-type but not Axl-/- or IL-15Ralpha-/- mice [6].
• We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions [2].
• In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion [2].
• Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival [2].

Biological context of Axl

• Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase [7].
• Surprisingly, GAS6-stimulated 32D-Axl cells exhibited no blockage to apoptosis or mitogenic response which is correlated with the absence of Ras/ERK activation [8].
• In contrast, a stimulatory anti-Axl antibody increased activation responses to these agonists, suggesting a potentiating role for Gas6 in platelet activation [9].
• Gas6 and Axl upregulation was a prominent but nonspecific finding in these renal diseases [10].
• Microarray analysis revealed that transcripts for the Axl and Mer receptor tyrosine kinases are expressed at high levels in O4+-immunopanned oligodendrocytes isolated from second trimester human fetal spinal cord [11].

Anatomical context of Axl

• These results suggest that Dtk and Ufo are likely to be involved in the regulation of hematopoiesis, particularly during the embryonic stages of blood cell development [12].
• Gas6-Axl interactions have been shown to mediate cell survival in vascular endothelium [13].
• These results collectively suggest that Axl, Tyro3 and Mer transmit signals that are essential for the generation of a functional NK cell repertoire [14].
• Gas6 mRNA is present in both spinal motor neurons and large neurons of the dorsal root ganglia, and neural injury has been reported to upregulate Rse/Axl in the schwann cell [15].
• In summary, Axl is an important signaling mediator for oxidative stress in cultured vascular smooth muscle cells and intact vessels and may represent an important therapeutic target for vascular remodeling and response to injury [16].

Associations of Axl with chemical compounds

• Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17 [7].
• Confocal microscopy and Western blot showed Ang II-dependent Gas6 and Axl expression [10].
• In our previous study, we demonstrated that Gas6 specifically binds to phosphatidylserine (PS) and links Axl-expressing cells to the PS-coated surface [17].
• Because oxidative stress is known to play a major role in remodeling of injured vessels, we hypothesized that H(2)O(2) might activate Axl by promoting autophosphorylation [16].
• In intact vessels Axl was phosphorylated by H(2)O(2), and Axl phosphorylation was inhibited by warfarin treatment in balloon-injured carotids [16].
• We demonstrate that the AP-2alpha regulated gene Axl is an essential player in GN-11 neuron migration [18].

Regulatory relationships of Axl

• Pharmacological blockade of the phospholipase C gamma effectors, protein kinase C or calcium/calmodulin protein kinase II, had no effect on Gas6/Axl signaling to promote Rac activation or stimulate cytoskeletal reorganization and migration [19].

Other interactions of Axl

• Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum [7].
• Oligodendrocyte cultures established from wild-type and Rse(-/-) mice, but not from Axl(-/-) mice, were also protected from TNFalpha-induced cell death when maintained in rhgas6 [20].
• Axl is a receptor tyrosine kinase that contains both immunoglobulin and fibronectin III repeats in its extracellular domain reminiscent of cell adhesion molecules [21].
• Transforming activity of retroviral genomes encoding Gag-Axl fusion proteins [22].

Analytical, diagnostic and therapeutic context of Axl

• Axl was not expressed in the testicular somatic cells by RT-PCR or Northern blot analysis [23].
• Quantitative immunohistochemistry of Axl(-/-) LCA showed increased apoptosis compared with Axl(+/+) (5-fold) [24].
• Vascular remodeling in mice deficient in Axl (Axl(-/-)) and wild-type littermates (Axl(+/+)) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery [24].
• A recent series of studies has revealed the in vivo roles of Gas6 and its receptor Axl in the progression of acute and chronic glomerulonephritis, diabetic nephropathy, chronic allograft rejection, and human kidney diseases [25].

References