Axl

AXL, short for AXL receptor tyrosine kinase, is a transmembrane protein that belongs to the TAM family of receptor tyrosine kinases, together with TYRO3 and MERTK. It is encoded by the human AXL gene and was identified as the cellular counterpart of the v-axl oncogene. The receptor is activated primarily by the ligand Gas6, with Protein S capable of activating AXL in certain contexts. AXL plays roles in development, immune regulation, and cancer.

The receptor has an extracellular region containing immunoglobulin-like and fibronectin type III domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding induces autophosphorylation and triggers signaling cascades such as PI3K-Akt, MAPK/ERK, and sometimes NF-κB. These pathways promote cell survival, proliferation, migration, and resistance to apoptosis. In immune cells, Gas6-AXL signaling can modulate inflammatory responses and facilitate the phagocytosis of apoptotic cells.

Expression of AXL is broad, with notable presence in various tissues, endothelial cells, and immune cells. In oncology, AXL is frequently overexpressed in diverse cancers and is associated with tumor progression, metastasis, and resistance to therapies, including EGFR inhibitors. AXL signaling also contributes to immune evasion in the tumor microenvironment and has been implicated in autoimmunity and inflammatory diseases.

Therapeutically, AXL is an active drug target. Several small-molecule inhibitors with selectivity for AXL are in clinical development, including bemcentinib (BGB324); other inhibitors may target AXL alongside additional kinases. These agents are being explored in combination therapies to overcome drug resistance and enhance anti-tumor activity.