The MAP4K4-STRIPAK complex promotes growth and tissue invasion in medulloblastoma

Abstract

Proliferation and motility are mutually exclusive biological processes associated with cancer that depend on precise control of upstream signaling pathways with overlapping functionalities. We find that STRN3 and STRN4 scaffold subunits of the STRIPAK complex interact with MAP4K4 for pathway regulation in medulloblastoma. Disruption of the MAP4K4-STRIPAK complex impairs growth factor-induced migration and tissue invasion and stalls YAP/TAZ target gene expression and oncogenic growth. The migration promoting functions of the MAP4K4-STRIPAK complex involve the activation of novel PKCs and the phosphorylation of the membrane targeting S157 residue of VASP through MAP4K4. The anti-proliferative effect of complex disruption is associated with reduced YAP/TAZ target gene expression and results in repressed tumor growth in the brain tissue. This dichotomous functionality of the STRIPAK complex in migration and proliferation control acts through MAP4K4 regulation in tumor cells and provides relevant mechanistic insights into novel tumorigenic functions of the STRIPAK complex in medulloblastoma.