Axl-dependent signalling: A clinical update

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Clinical Science (Impact Factor: 5.6). 04/2012; 122(8):361-8. DOI: 10.1042/CS20110411
Source: PubMed


Axl is a receptor tyrosine kinase that was originally cloned from cancer cells. Axl belongs to the TAM (Tyro3, Axl and Mertk) family of receptor tyrosine kinases. Gas6 (growth-arrest-specific protein 6) is a ligand for Axl. Activation of Axl protects cells from apoptosis, and increases migration, aggregation and growth through multiple downstream pathways. Up-regulation of the Gas6/Axl pathway is more evident in pathological conditions compared with normal physiology. Recent advances in Axl receptor biology are summarized in the present review. The emphasis is given to translational aspects of Axl-dependent signalling under pathological conditions. In particular, inhibition of Axl reduces tumorigenesis and prevents metastasis as well. Axl-dependent signals are important for the progression of cardiovascular diseases. In contrast, deficiency of Axl in innate immune cells contributes to the pathogenesis of autoimmune disorders. Current challenges in Axl biology are related to the functional interactions of Axl with other members of the TAM family or other tyrosine kinases, mechanisms of ligand-independent activation, inactivation of the receptor and cell-cell interactions (with respect to immune cells) in chronic diseases.

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    • "AXL was originally cloned from patients with chronic myelogenous leukemia and, when overexpressed, it exhibits transforming potential [33]. AXL overexpression has been reported in a variety of human cancers, being associated with tumor invasiveness and metastasis [35] [36] [37] [38]. "
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    ABSTRACT: Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.
    Experimental Cell Research 01/2015; 332(1). DOI:10.1016/j.yexcr.2015.01.009 · 3.25 Impact Factor
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    • "The binding of Gas6 and Axl induces activation of the Gas6/Axl signal pathway in multiple cellular functions, including cell proliferation and migration [3] [4]. The Axl receptor is overexpressed in cancers, is correlated with multidrug resistance and contributes to tumorigenesis by regulating migration and tumor growth [3] [4] [5] [6] [7]. Furthermore, increased levels of Axl protein have been observed in renal cell carcinoma compared with the normal kidney pair [8]. "
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    ABSTRACT: Withaferin A, a withanolide derived from the medicinal plant Withania somnifera, has been reported to exhibit anti-tumorigenic activity against various cancer cells. In this study, we show that withaferin A inhibits the constitutive and recombinant human growth-arrest-specific protein 6 (rhGas6)-induced phosphorylation of Axl and STAT3. In addition, withaferin A also induces the down-regulation of Axl protein expression in a lysosome-dependent manner and inhibits rhGas6-induced wound healing and cell migration. Furthermore, the overexpression of Axl attenuates withaferin A-induced apoptosis. Taken together, the data from the present study indicate that the withaferin A-mediated down-regulation of the Gas6/Axl signaling pathway mediates the inhibition of cell migration and the induction of apoptosis.
    Biochemical and Biophysical Research Communications 08/2014; 451(3). DOI:10.1016/j.bbrc.2014.08.018 · 2.30 Impact Factor
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    • "Axl is a member of the TAM (Tyro3, Axl and Mertk) family of receptor tyrosine kinases which are all activated by the ligand Gas6. Binding of Gas6 to Axl leads to receptor dimerisation, autophosphorylation and activation of downstream signalling pathways including PI3-Kinase/Akt and Erk1/2 resulting in pro-survival and proliferative responses, respectively [5],[6]. "
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    ABSTRACT: Chronic kidney disease (CKD) is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1%) diet to Axl+/+ and Axl-/- mice. Plasma Gas6 (Axl' ligand), renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl-/- mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl-/- mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl-/- mice. Vascular calcification was not induced in Axl+/+ or Axl-/- mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD.
    PLoS ONE 07/2014; 9(7):e102096. DOI:10.1371/journal.pone.0102096 · 3.23 Impact Factor
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