FAM150A and FAM150B bind to the ECD of ALK and, in addition to activation of wild-type ALK, are able to drive ‘superactivation’ of activated ALK mutants from neuroblastoma. The GR of the ALK receptor ECD is important for FAM150 activation, and monoclonal antibodies (mAb) recognizing the GR of ALK are able to inhibit activation of ALK by FAM150A. In conclusion, our data show that ALK is robustly activated by FAM150A/B finally providing an answer to the identity of the elusive ligands for this RTK. Here, ALK is linked to neuroblastoma.