Anaplastic lymphoma kinase (ALK), discovered in 1994, was first described as a fusion partner in the chromosomal translocation in anaplastic large cell lymphoma (ALCL), from which ALK takes its name.Several years passed before the unveiling of the full-length ALK receptor tyrosine kinase (RTK), which consists of an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain.The characterisation of downstream ALK signalling events has focused on fusion proteins such as NPM-ALK and EML4-ALK, where kinase activation and signalling is driven by oligomerisation.Wild-type ALK is a membrane-bound receptor.In general, ALK activates multiple signalling pathways, such as the PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5, JAKSTAT and MAPK pathways.Activation of adaptor proteins and other cellular proteins, such as PTPN11, Src, FRS2, Shc-GRB2, IRS2, GSK-3a and FAK, has been observed downstream of ALK, indicating roles for alternative pathways. Other reported downstream ALK targets include BIM, p27, cyclin D2, NIPA, RAC1, CDC42, p130CAS, SHP1 and FYVE finger containing phosphoinositide kinase (PIKFYVE).ALK kinase signalling across different tumour types, such as NSCLC, ALCL and neuroblastoma, shares many features, but also exhibits certain differences.


1.Hallberg B, Palmer RH. Ann Oncol. 2016 Sep;27 Suppl 3:iii4-iii15.