title: The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics.
abstract: Phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P(2)) and its phosphorylated product PI 3,4,5-triphosphate (PI(3,4,5)P(3)) are two major phosphoinositides concentrated at the plasma membrane. Their levels, which are tightly controlled by kinases, phospholipases, and phosphatases, regulate a variety of cellular functions, including clathrin-mediated endocytosis and receptor signaling. In this study, we show that the inositol 5-phosphatase SHIP2, a negative regulator of PI(3,4,5)P(3)-dependent signaling, also negatively regulates PI(4,5)P(2) levels and is concentrated at endocytic clathrin-coated pits (CCPs) via interactions with the scaffold protein intersectin. SHIP2 is recruited early at the pits and dissociates before fission. Both knockdown of SHIP2 expression and acute production of PI(3,4,5)P(3) shorten CCP lifetime by enhancing the rate of pit maturation, which is consistent with a positive role of both SHIP2 substrates, PI(4,5)P(2) and PI(3,4,5)P(3), on coat assembly. Because SHIP2 is a negative regulator of insulin signaling, our findings suggest the importance of the phosphoinositide metabolism at CCPs in the regulation of insulin signal output.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Fubito
authors.initials: F
authors.lastname: Nakatsu
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.forename: Louise
authors.initials: L
authors.lastname: Lucast
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.forename: Jan
authors.initials: J
authors.lastname: Domin
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.forename: Derek
authors.initials: D
authors.lastname: Toomre
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000378:metabolism*; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism*; D004705:Endocytosis; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*
chemical_list: D002966:Clathrin; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases