Author/Authors :
Yi، نويسنده , , Chunling and Troutman، نويسنده , , Scott and Fera، نويسنده , , Daniela and Stemmer-Rachamimov، نويسنده , , Anat and Avila، نويسنده , , Jacqueline L. and Christian، نويسنده , , Neepa and Persson، نويسنده , , Nathalie Luna and Shimono، نويسنده , , Akihiko and Speicher، نويسنده , , David W. and Marmorstein، نويسنده , , Ronen and Holmgren، نويسنده , , Lars and Kissil، نويسنده , , Joseph L.، نويسنده ,
Abstract :
Summary
rlin/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.
