Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

摘要

The gene AXL, a name derived from the Greek word anexelekto ("uncontrolled") was first isolated from chronic myelogenous leukemia, and its overexpression was found to induce fibroblast transformation with simultaneous appearance of a 140-kDa tyrosine-phosphorylated protein (1). AXL is also known as adhesion-related kinase (2), Tyro7 (3), orunknown function (4). AXL belongs to the TAM family of receptor tyrosine kinases (RTK), which also includes Tyro3 and MERTK. TAM receptors have pleiotropic functions in many biologic processes, such as coagulation, immune response, and cancer progression (5).Theyshare among their members 16% to 31% of their extracellular amino acid sequence and 54% to 59% of their intracellular domain (6). Autophosphorylation of the intracellular tyrosine kinase domain of AXL occurs following receptor activation and is mediated either by ligand-dependent or ligand-independent receptor dimeriza-tion. Growth arrest-specific protein 6 (Gas6) has been identified as the only ligand that binds the extracellular domain of AXL (7-9). Receptor homodimerization or heterodimerization with other RTKs, such as EGFR (10), results in rapid phosphorylation of AXL and the activation of a number of downstream effectors (see "AXL signaling pathway").