Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L

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Abstract
Neurofibromatosis 2 (NF2) is a tumor suppressor, although the molecular mechanism accounting for this effect remains unknown. Here, we show that merlin exerts its activity by inhibiting phosphatidylinositol 3-kinase (PI3-kinase), through binding to PIKE-L. Wild-type merlin, but not patient-derived mutant (L64P), binds PIKE-L and inhibits PI3-kinase activity. This suppression of PI3-kinase activity results from merlin disrupting the binding of PIKE-L to PI3-kinase. In addition, merlin suppression of PI3-kinase activity as well as schwannoma cell growth is abrogated by a single PIKE-L point mutation (P187L) that cannot bind merlin but can still activate PI3-kinase. Knocking down PIKE-L with RNA interference abolishes merlin9s tumor-suppressive activity. Our data support the hypothesis that PIKE-L is an important mediator of merlin growth suppression.