PI4K2A promotes cancer cell motility by regulating c-MET recycling

Abstract Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality, largely due to metastatic disease. Cell surface proteins regulate tumor–stroma interactions and metastatic progression, and their abundance is dynamically controlled by secretion and endocytic recycling pathways. Using cancer cell surfaceome profiling, we identified phosphatidylinositol 4-kinase type 2α (PI4K2A) as a key regulator of cell surface protein levels. PI4K2A controls the membrane abundance and activity of receptor tyrosine kinases, including the c-MET proto-oncogene (MET), thereby promoting cancer cell motility - an early step in metastasis. Mechanistically, PI4K2A interacts with MET and directs endocytosed MET to RAB14-positive recycling endosomes, enhancing MET recycling and activation. Notably, this pro-recycling and pro-migratory function is independent of PI4K2A kinase activity and instead depends on its interaction with MET and RAB14 endosomes. These findings reveal a kinase-independent role for PI4K2A in regulating the cancer cell surfaceome.