title: Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis.
abstract: Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and solutes are internalized into cells. Macropinocytosis starts with the formation of membrane ruffles at the plasma membrane and ends with their closure. The transient and sequential emergence of phosphoinositides PI(3,4,5)P3 and PI(3,4)P2 in the membrane ruffles is essential for macropinocytosis. By making use of information in the Caenorhabditis elegans mutants defective in fluid-phase endocytosis, we found that mammalian phosphoinositide phosphatase MTMR6 that dephosphorylates PI(3)P to PI, and its binding partner MTMR9, are required for macropinocytosis. INPP4B, which dephosphorylates PI(3,4)P2 to PI(3)P, was also found to be essential for macropinocytosis. These phosphatases operate after the formation of membrane ruffles to complete macropinocytosis. Finally, we showed that KCa3.1, a Ca(2+)-activated K(+) channel that is activated by PI(3)P, is required for macropinocytosis. We propose that the sequential breakdown of PI(3,4,5)P3 → PI(3,4)P2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.
authors.affiliation: Department of Health Chemistry and Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maekawa
authors.forename: Shimpei
authors.initials: S
authors.lastname: Terasaka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Kawai
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Araki
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D010873:Pinocytosis / Q000502:physiology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018129:Phosphatidylinositol Phosphates; D034741:RNA, Small Interfering; D010744:Phosphoric Monoester Hydrolases; C513490:MTMR6 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase