title: FERM domain phosphoinositide binding targets merlin to the membrane and is essential for its growth-suppressive function.
abstract: The neurofibromatosis type 2 tumor suppressor protein, merlin, is related to the ERM (ezrin, radixin, and moesin) family of plasma membrane-actin cytoskeleton linkers. For ezrin, phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding to the amino-terminal FERM domain is required for its conformational activation, proper subcellular localization, and function, but less is known about the role of phosphoinositide binding for merlin. Current evidence indicates that association with the membrane is important for merlin to function as a growth regulator; however, the mechanisms by which merlin localizes to the membrane are less clear. Here, we report that merlin binds phosphoinositides, including PIP(2), via a conserved binding motif in its FERM domain. Abolition of FERM domain-mediated phosphoinositide binding of merlin displaces merlin from the membrane and releases it into the cytosol without altering the folding of merlin. Importantly, a merlin protein whose FERM domain cannot bind phosphoinositide is defective in growth suppression. Retargeting the mutant merlin into the membrane using a dual-acylated amino-terminal decapeptide from Fyn is sufficient to restore the growth-suppressive properties to the mutant merlin. Thus, FERM domain-mediated phosphoinositide binding and membrane association are critical for the growth-regulatory function of merlin.
authors.affiliation: Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, 3125 Eden Avenue, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Timmy
authors.initials: T
authors.lastname: Mani
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hennigan
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Foster
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Conrady
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
authors.forename: Wallace
authors.initials: W
authors.lastname: Ip
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence
chemical_list: D025581:Neurofibromin 2; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols