A Tight Junction-Associated Merlin-Angiomotin Complex Mediates Merlin's Regulation of Mitogenic Signaling and Tumor Suppressive Functions

SummaryThe Merlin/NF2 tumor suppressor restrains cell growth and tumorigenesis by controlling contact-dependent inhibition of proliferation. We have identified a tight-junction-associated protein complex comprising Merlin, Angiomotin, Patj, and Pals1. We demonstrate that Angiomotin functions downstream of Merlin and upstream of Rich1, a small GTPase Activating Protein, as a positive regulator of Rac1. Merlin, through competitive binding to Angiomotin, releases Rich1 from the Angiomotin-inhibitory complex, allowing Rich1 to inactivate Rac1, ultimately leading to attenuation of Rac1 and Ras-MAPK pathways. Patient-derived Merlin mutants show diminished binding capacities to Angiomotin and are unable to dissociate Rich1 from Angiomotin or inhibit MAPK signaling. Depletion of Angiomotin in Nf2−/− Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo.

► Merlin forms a tight-junction associated complex with Angiomotin, Patj, and Pals1 ► Merlin negatively regulates Rac1 by interfering with Rich1/Angiomotin interaction ► Merlin modulates MAPK signaling through the Rac1-Pak axis ► Angiomotin is required for tumorigenesis subsequent to loss of NF2