Subcellular proteomic analysis of the DDR2 interactome in a neuronal cell model exposed to Aβ42.

Receptor tyrosine kinases (RTKs) are increasingly understood to signal beyond the plasma membrane. However, the role of Discoidin domain receptor 2 (DDR2), which is activated by collagen, in neurodegeneration remains poorly understood. This study uses immunoprecipitation followed by mass spectrometry on cytoplasmic and nuclear fractions from a neuronal cell model to show that Aβ42 exposure is associated with a compartment-specific reorganization of DDR2-associated protein complexes, characterized by increased nuclear representation. This reveals a unique nuclear DDR2 interactome under amyloidogenic conditions. By exploring this non-canonical, compartment-specific DDR2 signaling pathway, our results offer new insights into how receptor signaling networks may be altered in Alzheimer's disease pathology. Additionally, we identify DDR2-related nuclear interactions as potential sites of dysregulation in neurodegeneration.