ALKAL2 (ALK and LTK ligand 2) functions as a cytokine that serves as a physiological ligand for receptor tyrosine kinases ALK and LTK, leading to their activation through distinct mechanisms 1. The protein can form complexes with ALK in both 2:1 and 2:2 stoichiometries, with structural studies revealing that ALK undergoes ligand-induced rearrangement and adopts an orientation parallel to the membrane surface upon ALKAL2 binding 12. ALKAL2 is particularly enriched in TRPV1+ sensory neurons and peptidergic nociceptors, where inflammation or injury enhances its expression 3. The ALKAL2/ALK signaling axis plays critical roles in pain mediation, with ALKAL2 promoting nociceptor sensitization and contributing to thermal hyperalgesia and mechanical allodynia 3. In cancer contexts, ALKAL2 forms an autocrine loop with ALK in consensus molecular subtype 1 colon cancer, driving tumor growth and invasion 4. The ligand also contributes to neuroblastoma cell growth by stabilizing SLC3A2 expression via MARCH11 regulation 5 and promotes colitis-associated colorectal cancer progression through neuronal signaling 6. Clinically, elevated plasma ALKAL2 levels are associated with coronary artery disease severity in type 2 diabetes patients 7, and ALK inhibitors like crizotinib and lorlatinib show therapeutic potential for targeting ALKAL2-driven pathways in cancer and pain management 34.