ALKAL1 (ALK And LTK Ligand 1)

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.

Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.

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.

Blocking AhR-MerTK signaling also improved the efficacy of anti-PD-L1 therapy. Collectively, our study revealed the regulatory mechanism of MerTK-mediated efferocytosis of TAMs, thus furthering our understanding of macrophage polarization and providing new strategies for immunotherapy of melanoma.