AXL Tyrosine Kinases: A Growing Isoform Family That Promotes Cancer Pathogenesis.

Abstract

The AXL receptor tyrosine kinase is implicated in various cancers, and its expression is linked with poor survival and resistance to therapy. In this review, we overview the complexity of AXL receptor signaling, emphasizing the distinctions between the AXL isoforms. Recent studies have identified a third AXL isoform, AXL3, which lacks the growth arrest-specific 6-binding domains found in AXL1 and AXL2. This unique structure of AXL3 suggests alternative activation and signaling mechanisms. Activation of AXL1/2 typically occurs through ligand binding, dimerization, and phosphorylation, leading to downstream signaling via pathways including PI3K/AKT, MAPK/ERK, JAK/STAT, and NF-κB. Unlike other oncogenic kinases, in which overexpression and overactivation can be attributed to genomic alterations, AXL upregulation is generally caused by nongenetic mechanisms. Analysis of the promoter region of AXL3 reveals potential binding sites for transcription factors such as KLF16 and MEIS3, which are linked to oncogenic pathways. AXL signaling in cancer promotes cell survival, proliferation, migration, and immune evasion. Therefore, inhibiting AXL by therapeutic approaches has been explored with varying results. Elucidating the functions and regulatory mechanisms of the different AXL isoforms is imperative for developing effective targeted therapies that improve outcomes in AXL-driven cancers.