title: The PH domain proteins IPIP27A and B link OCRL1 to receptor recycling in the endocytic pathway.
abstract: Mutation of the inositol polyphosphate 5-phosphatase OCRL1 results in two disorders in humans, namely Lowe syndrome (characterized by ocular, nervous system, and renal defects) and type 2 Dent disease (in which only the renal symptoms are evident). The disease mechanisms of these syndromes are poorly understood. Here we identify two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27 kDa (IPIP27)A and B (also known as Ses1 and 2), that also bind the related 5-phosphatase Inpp5b. The IPIPs bind to the C-terminal region of these phosphatases via a conserved motif similar to that found in the signaling protein APPL1. IPIP27A and B, which form homo- and heterodimers, localize to early and recycling endosomes and the trans-Golgi network (TGN). The IPIPs are required for receptor recycling from endosomes, both to the TGN and to the plasma membrane. Our results identify IPIP27A and B as key players in endocytic trafficking and strongly suggest that defects in this process are responsible for the pathology of Lowe syndrome and Dent disease.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Noakes
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009800:Oculocerebrorenal Syndrome / Q000201:enzymology / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism*; D055571:Secretory Pathway; D022621:Shiga Toxin / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: C548332:PHETA1 protein, human; C548333:PHETA2 protein, human; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D033921:Vesicular Transport Proteins; D022621:Shiga Toxin; D006867:Hydrolases; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human