Figure 1. ALK activation mechanisms.

Activation of ALK signaling is rare in most adult tissues but is active in the development of the gut and nervous system. Activation of native ALK is via ligand-induced dimerization and resultant autophosphorylation. In drosophila the ligand for ALK is Jelly Belly, whereas in mammals pleiotrophin and midkine have been reported as ligands for ALK. ^11,12,86,87 In most ALK+ cancers, ALK expression is re-instituted through the active promoter of a 5′ partner that fuses with the kinase-encoding region of ALK. The resulting fusion gene then generates a fusion protein that can dimerize via domains in the 5′ partner mimicking ligand induced activation. ¹⁴ Rarely, mutations in the kinase domain of full length ALK can also promote primary oncogenic activation of ALK (Box 1). ALK phosphorylation results in activation of downstream signaling pathways including JAK/STAT, PI3K/AKT, and MEK/ERK, which can promote cell proliferation, differentiation, and provide anti-apoptotic signals. ⁸⁸