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, 122 (8), 361-8

Axl-dependent Signalling: A Clinical Update


Axl-dependent Signalling: A Clinical Update

Vyacheslav A Korshunov. Clin Sci (Lond).


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.


Figure 1
Figure 1. Axl receptor structure
The extracellular domain of Axl has two immunoglobulin (Ig)-like (black bracket) and two fibronectin (FN) type III-like (blue) domains. An intracellular kinase domain (yellow) contains autophosphorylation sites (Y779, Y821, Y866). A product of growth arrest-specific protein 6 (Gas6; green) can activate Axl. A dimerization of two 1:1 Gas6/Axl complexes is required for signal transduction.
Figure 2
Figure 2. Mechanisms of Axl receptor activation/inactivation
A, Ligand-induced activation of Axl by Gas6 (green color). Initial formation of a high affinity 1:1 Gas6/Axl complex followed by dimerization of two 1:1 Gas6/Axl complexes. B, A homophilic binding of extracellular domains of Axl expressed on neighboring cells leads to aggregation, especially in excess of Axl. C, A ligand-independent homophilic dimerization of Axl and autophosphorylation in response to ROS (red color). D, A proteolytic cleavage of sAxl by unknown protease.
Figure 3
Figure 3. Axl receptor signal transduction
Axl controls cell survival, migration, proliferation and inflammation (red color). Major downstream targets of Axl are shown in circles and ellipses. Thick arrows show direction of signals. Thin lines show inhibitory effects of Axl. Activation of SHP-2 is responsible for Gas6/Axl-mediated VEGFR2 inhibition.
Figure 4
Figure 4. Axl signaling associates with pathological conditions
Axl is involved in immune cell functions that inhibit chronic immune activation (blue color). Axl affects tumor cell function and promotes cancer (green color). Activation of Axl is critical for advanced cardiovascular diseases (red color). Thin arrows show potential effects of Axl signaling on cell-to-cell interaction during three types of pathological conditions.

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