Active Merlin Binds RalB to Regulate Exocytosis

Loss of NF2 tumor suppressor activity causes NF2-related schwannomatosis. Proximity biotinylation identified proteins proximal to Merlin isoform 1 and isoform 2 at confluence, when Merlin is active, but not in sub-confluent, growing cells. These data confirmed Merlin involvement in cell-cell and cell-substrate junctions, identified new signal transduction pathways, and highlighted a role for Merlin in intracellular transport. Direct binding assays identified the small GTPases RalA and RalB as high affinity PIP ₂ -dependent Merlin binding proteins that co-localized with RalA/B on the plasma membrane. Merlin loss resulted in aberrant activation of RalA and RalB at high cell density. Merlin competitively inhibited RalB binding to its exocyst effectors Sec5 and Exo84 and regulated the kinetics of exocytosis in a RalB dependent manner. Thus, RalB is a novel binding partner for active Merlin, and the RalA/B pathway is a possible therapeutic target to treat NF2-related schwannoma.