title: The cell fate determinant numb interacts with EHD/Rme-1 family proteins and has a role in endocytic recycling.
abstract: The adaptor protein Numb is necessary for the cell fate specification of progenitor cells in the Drosophila nervous system. Numb is evolutionarily conserved and previous studies have provided evidence for a similar functional role during mammalian development. The Numb protein has multiple protein-protein interaction regions including a phosphotyrosine binding (PTB) domain and a carboxy-terminal domain that contains conserved interaction motifs including an EH (Eps15 Homology) domain binding motif and alpha-adaptin binding site. In this study we identify the EHD/Rme-1/Pincher family of endocytic proteins as Numb interacting partners in mammals and Drosophila. The EHD/Rme-1 proteins function in recycling of plasma membrane receptors internalized by both clathrin-mediated endocytosis and a clathrin-independent pathway regulated by ADP ribosylation factor 6 (Arf6). Here we report that Numb colocalizes with endogenous EHD4/Pincher and Arf6 and that Arf6 mutants alter Numb subcellular localization. In addition, we present evidence that Numb has a novel function in endosomal recycling and intracellular trafficking of receptors.
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Smith
authors.forename: Sascha E
authors.initials: SE
authors.lastname: Dho
authors.forename: Julie
authors.initials: J
authors.lastname: Donaldson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Tepass
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000032:analysis / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000276:immunology; D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D007605:Juvenile Hormones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D025941:Protein Interaction Mapping; D034622:RNA Interference; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D033921:Vesicular Transport Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000089982:ADP-Ribosylation Factor 6; D033942:Adaptor Proteins, Vesicular Transport; D029721:Drosophila Proteins; D007605:Juvenile Hormones; C496522:Past1 protein, Drosophila; D015375:Receptors, Interleukin-2; D033921:Vesicular Transport Proteins; C060606:numb protein, Drosophila; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human