title: Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β.
abstract: Transforming growth factor-β (TGF-β) ligands activate Smad-mediated and noncanonical signaling pathways in a cell context-dependent manner. Localization of signaling receptors to distinct membrane domains is a potential source of signaling output diversity. The tumor suppressor/endocytic adaptor protein disabled-2 (Dab2) was proposed as a modulator of TGF-β signaling. However, the molecular mechanism(s) involved in the regulation of TGF-β signaling by Dab2 were not known. Here we investigate these issues by combining biophysical studies of the lateral mobility and endocytosis of the type I TGF-β receptor (TβRI) with TGF-β phosphoprotein signaling assays. Our findings demonstrate that Dab2 interacts with TβRI to restrict its lateral diffusion at the plasma membrane and enhance its clathrin-mediated endocytosis. Small interfering RNA-mediated knockdown of Dab2 or Dab2 overexpression shows that Dab2 negatively regulates TGF-β-induced c-Jun N-terminal kinase (JNK) activation, whereas activation of the Smad pathway is unaffected. Moreover, activation of JNK by TGF-β in the absence of Dab2 is disrupted by cholesterol depletion. These data support a model in which Dab2 regulates the domain localization of TβRI in the membrane, balancing TGF-β signaling via the Smad and JNK pathways.
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Keren E
authors.initials: KE
authors.lastname: Shapira
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Hirschhorn
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Barzilay
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Nechama I
authors.initials: NI
authors.lastname: Smorodinsky
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel henis@post.tau.ac.il marceloe@post.tau.ac.il.
authors.forename: Yoav I
authors.initials: YI
authors.lastname: Henis
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel henis@post.tau.ac.il marceloe@post.tau.ac.il.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D002966:Clathrin; D004705:Endocytosis / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002966:Clathrin; C102885:DAB2 protein, human; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; D048031:JNK Mitogen-Activated Protein Kinases