Cooperation of Striatin 3 and MAP4K4 promotes growth and tissue invasion

Abstract MAP4K4 has been correlated with increased cell motility and reduced proliferation in mammalian cells. The regulation of this dichotomous functionality of MAP4K4 in tumor cells remained elusive. We find that MAP4K4 interacts with striatin 3 and 4 (STRN3/4) in medulloblastoma and that STRN3 and MAP4K4 exert opposing functions in Hippo tumor suppressor signaling and clonal growth. However, depletion of either STRN3 or MAP4K4 reduces migration and tissue invasion, and concomitant loss of both proteins abrogates tumor cell growth in the cerebellar tissue. Mechanistically, STRN3 couples MAP4K4 to the protein phosphatase 2A, which inactivates growth repressing activities of MAP4K4. In parallel, STRN3 enables growth factor-induced PKCθ activation and the direct phosphorylation of VASPS157 by MAP4K4, which both are necessary for efficient migration and tissue invasion. The VASPS157 directed activity of MAP4K4 and STRN3 requires the CNH domain of MAP4K4, which we also found to mediate its interaction with striatins. Thus, STRN3 is a master regulator of growth factor-activated MAP4K4 function and disruption of its cooperation with MAP4K4 reactivates Hippo signaling and represses tissue invasion in medulloblastoma.