title: A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions.
abstract: The 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.
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Chunling
authors.initials: C
authors.lastname: Yi
authors.forename: Scott
authors.initials: S
authors.lastname: Troutman
authors.forename: Daniela
authors.initials: D
authors.lastname: Fera
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Avila
authors.forename: Neepa
authors.initials: N
authors.lastname: Christian
authors.forename: Nathalie Luna
authors.initials: NL
authors.lastname: Persson
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Lars
authors.initials: L
authors.lastname: Holmgren
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kissil
mesh_terms: D000595:Amino Acid Sequence; D000091082:Angiomotins; D000818:Animals; D049109:Cell Proliferation; D020690:GTPase-Activating Proteins / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D025581:Neurofibromin 2 / Q000502:physiology*; D009703:Nucleoside-Phosphate Kinase / Q000502:physiology; D010525:Peripheral Nerves / Q000737:chemistry; D012583:Schwann Cells / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*; D062725:Tight Junction Proteins; D019108:Tight Junctions / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: C423985:AMOT protein, human; C504466:ARHGAP17 protein, human; C511047:Amot protein, mouse; D000091082:Angiomotins; D020690:GTPase-Activating Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025581:Neurofibromin 2; C107903:PATJ protein, human; D062725:Tight Junction Proteins; D025521:Tumor Suppressor Proteins; D009703:Nucleoside-Phosphate Kinase; C501307:MPP5 protein, human; D020830:rac1 GTP-Binding Protein