ALK (anaplastic lymphoma kinase) is a neuronal receptor tyrosine kinase essential for central and peripheral nervous system development and differentiation 1. The receptor comprises an extracellular region, transmembrane helix, and intracellular tyrosine kinase domain 1. ALK activation occurs through ligand binding by ALKAL2 (but not ALKAL1 as a potent physiological ligand) 1, inducing receptor dimerization and tyrosine kinase activation via an unusual membrane-proximal orientation mechanism 1. Upon activation, ALK phosphorylates substrates including CBL, FRS2, IRS1, and SHC1, leading to MAPK/ERK pathway activation and NF-κB signaling 1. ALK also regulates energy homeostasis in hypothalamic neurons as a negative regulator of white adipose tissue lipolysis [UniProt]. Clinically, ALK is a major oncogenic driver in several malignancies. EML4-ALK translocations account for ~85% of ALK fusions in non-small cell lung cancer (NSCLC), with variants 1 and 3 being most prevalent, showing differential response to ALK tyrosine kinase inhibitors 2. ALK mutations drive pediatric neuroblastoma through POSTN and WNT signaling feedforward loops 3. ALK gene fusions also characterize anaplastic large cell lymphoma and ALK-positive large B-cell lymphoma 4. Multiple ALK inhibitors have demonstrated clinical efficacy in metastatic ALK-positive NSCLC 5.