MAP4K4 determines cancer cell phenotype by controlling the plasma membrane-associated proteome

How the phenotype of Medulloblastoma (MB) tumor cells adapts in response to growth factor cues is poorly understood. We systematically determined alterations in the plasma membrane (PM)-associated proteome in growth factor-activated MB cells. We found that ligand-induced activation of c-MET receptor tyrosine kinase triggers specific internalization of c-MET and of membrane-associated and transmembrane proteins including nucleoside and ion transporters. In contrast, c-MET activation caused increased PM association of the PVR/CD155 adhesion and immunomodulatory receptor, promoting MB cell motility and tumor cell growth in the cerebellar tissue. Both increased and decreased PM association of a number of these proteins including PVR/CD155 is regulated by the Ser/Thr MAP4K4. We further identified Endophilin A proteins as potential regulators of this process downstream of MAP4K4 to contribute to HGF-induced invasion control. Together, our findings indicate a novel link between MAP4K4 overexpression in MB and the maintenance of a cellular phenotype associated with growth and invasiveness.