The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Abstract

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.

Keywords: ALCL; ALK; ALK-translocation proteins; EML4-ALK; NPM-ALK; NSCLC; epigenetics.

Figure 1

The Nucleophosmin 1 (NPM1)-ALK fusion protein resulting from the t(2;5)(p23;q25). Fusion of the NPM1 gene on chromosome 5 to the ALK gene on chromosome 2 results in the expression of NPM1-ALK, a constitutively activate tyrosine kinase. NPM1 encodes an oligomerisation domain (residues 1–117), a metal binding domain (MB; residues 104–115), two acidic amino acid clusters (AC: D and E amino acid rich domains which function as acceptor regions for nucleolar targeting signals; residues 120–132 and 161–188) and two nuclear localisation signals (NLS; residues 152–157 and 191–197). ALK encodes a Meprin/A5/protein tyrosine phosphatase domain (not shown), a ligand-binding site (residues 391–401) in the extracellular domain, a lipophilic transmembrane region (TM) and an intracellular domain that contains the tyrosine-kinase catalytic domain (TKD).

Figure 2

The NPM1-ALK fusion protein signals through the Janus protein tyrosine kinase (JAK)/STAT, Ras/mitogen-activated protein kinases (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt and phospholipase C gamma (PLC-γ) pathways. Adapted from Trigg et al., 2018 [23].

Figure 3

The NPM1-ALK fusion protein drives epigenetic change through DNA methyltransferase (DNMT), miRNA, and transcription factor (TF) expression and through interacting with nuclear proteins.