Fig. 2 ∣. ALK oncogenic signalling depends on the type of genetic alteration and cellular context.
a, Activation of full-length anaplastic lymphoma kinase (ALK) can be triggered by ALKAL1 and ALKAL2, which effectively stimulate ALK downstream signalling pathways. ALK amplifications and ALK point mutations in the kinase domain can bypass the dependence on ligand-mediated activation. Full-length amplified or mutated oncogenic ALK upregulates downstream signalling pathways, including Janus kinase (JAK)–signal transducer and activator of transcription (STAT), PI3K–AKT and MAPK pathways leading to aberrant survival and proliferation. The SHP2 phosphatase is a key effector of ALK activity, through direct binding at the SH2 domain and modulation of downstream pathways. In neuroblastoma, ALK-activating mutations and ALK amplification lead to ERK5 activation to promote proliferation68. They also lead to phosphorylation of ATR and CHK1, potentially through AKT (dashed arrow), to sustain an effective DNA damage response18. Therapeutic strategies for ALK+ tumours target key signalling pathways and are indicated in the figure. b, ALK fusions are generally localized to the cytoplasm and are activated independently of ligand. The constitutive kinase activity of ALK fusions triggers a context-dependent hyperactivation of ALK downstream pathways in tumour cells. Like full-length ALK, this includes JAK–STAT, PI3K–AKT and MAPK pathways in different tumour types. PTPN1 and PTPN2 phosphatases regulate SHP2 and ALK phosphorylation. Fused ALK represses mainly PTPN1 transcription110. SRC is activated by fused ALK and in turn triggers the MAPK pathway. The MAPK pathway has a fundamental role in all tumour types with ALK fusions. ALK fusions regulate the Rho GTPases and WASP only in anaplastic large-cell lymphoma (ALCL), leading to changes in cell morphology and migration. Moreover, ALK fusions in ALK+ ALCL induces expression of CD30 and represses CD45 through STAT3 and STAT5 signalling downstream of JAK. Therapeutic strategies are indicated. ADC, antibody–drug conjugate; C term, C terminus; N term, N terminus; NF-κB, nuclear factor-κB; PROTAC, proteolysis-targeting chimera; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor.