title: The adaptor-associated kinase 1, AAK1, is a positive regulator of the Notch pathway.
abstract: The Notch pathway is involved in cell-cell signaling during development and adulthood from invertebrates to higher eukaryotes. Activation of the Notch receptor by its ligands relies upon a multi-step processing. The extracellular part of the receptor is removed by a metalloprotease of the ADAM family and the remaining fragment is cleaved within its transmembrane domain by a presenilin-dependent γ-secretase activity. γ-Secretase processing of Notch has been shown to depend upon monoubiquitination as well as clathrin-mediated endocytosis (CME). We show here that AAK1, the adaptor-associated kinase 1, directly interacts with the membrane-tethered active form of Notch released by metalloprotease cleavage. Active AAK1 acts upstream of the γ-secretase cleavage by stabilizing both the membrane-tethered activated form of Notch and its monoubiquitinated counterpart. We propose that AAK1 acts as an adaptor for Notch interaction with components of the clathrin-mediated pathway such as Eps15b. Moreover, transfected AAK1 increases the localization of activated Notch to Rab5-positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization. These results suggest that after ligand-induced activation of Notch, the membrane-tethered form can be directed to different endocytic pathways leading to distinct fates.
authors.affiliation: Unité de Signalisation Moléculaire et Activation Cellulaire, CNRS URA 2582, CNRS URA 2582, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France. neetu.gupta@pasteur.fr
authors.forename: Neetu
authors.initials: N
authors.lastname: Gupta-Rossi
authors.forename: Sara
authors.initials: S
authors.lastname: Ortica
authors.forename: Vannary
authors.initials: V
authors.lastname: Meas-Yedid
authors.forename: Sara
authors.initials: S
authors.lastname: Heuss
authors.forename: Julien
authors.initials: J
authors.lastname: Moretti
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivo-Marin
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C486206:EPS15 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D010750:Phosphoproteins; D051880:Receptors, Notch; C451304:AAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D020696:rab5 GTP-Binding Proteins