ALKAL2 (ALK And LTK Ligand 2)

Elevated plasma ALKAL2 levels are an independent risk factor for T2DM CAD and are associated with the severity of CAD.

© 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

In vivo, mice treated with the ALK inhibitor lorlatinib at the onset of colitis exhibited a remarkable 90% reduction in tumor burden without significantly affecting overall inflammation. Moreover, activating TRPV1+ neurons using DREADD technology exacerbated tumor growth, whereas silencing these neurons significantly reduced it. These findings reveal that TRPV1+ nociceptors drive CAC progression via the ALKAL2/ALK pathway.

This new cryo-EM structure together with the crystal structures of ALK-ALKAL2 and LTK-ALKAL1 complexes with 2:1 stoichiometry reconciles a common receptor dimerization mode for ALK and LTK and provides direct evidence for the presence of an ALK-ALKAL2 complex with 2:1 stoichiometry next to the reported 2:2 stoichiometric assembly in the EMPIAR-10930 dataset. Finally, our analysis emphasizes the importance of public deposition of raw cryo-EM data to allow reanalysis and interpretation.

To investigate whether this interaction influences Wnt signaling in vitro, we conducted a Wnt signaling reporter assay (TOP Flash/FOP Flash) in neuroblastoma cells by introducing Rspo2, Wnt3a, and crizotinib, an ALK inhibitor. The results showed a decrease in the TOP/FOP ratio when ALK was inhibited. Collectively, our study reveals a novel role for ALK in enhancing Wnt signaling via R-spondins, providing new dimension into ALK-mediated oncogenesis.

These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK.

In contrast, a combination lorlatinib/AMXT-1501 treatment resulted in synergistic inhibition of cell growth in ALK-driven NB cell lines. Taken together, our results identify a novel role for the ALK receptor tyrosine kinase (RTK), working in concert with the MARCH11 E3 ligase, in regulating SLC3A2 protein stability and function in NB cells. The synergistic effect of combined ALK and polyamine transport inhibition shows that ALK/MARCH11/SLC3A2 regulation of amino acid transport is important for oncogenic growth and survival in NB cells.

Lastly, ALK expression is linked to reproductive functions, with potential implications for patients undergoing ALK inhibitor therapy. Further research is needed to better understand the complex interactions of ALK family receptors and Aug ligands and to repurpose targeted therapy for a wide range of human diseases.

Collectively, our data suggest that ALK inhibition by means of ALK-directed antibody-drug conjugate may represent an attractive target that may broaden the therapeutic opportunities for CMS1 colorectal cancer patients.