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PMID: 24591580 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 11 ·2014-03-18 ·Pages E978-87

Maekawa M, Terasaka S, Mochizuki Y, Kawai K, Ikeda Y, Araki N, Skolnik EY, Taguchi T, Arai H

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.

MeSH Terms
Animals Caenorhabditis elegans/metabolism,physiology Cell Line DNA Primers/genetics Humans Microscopy, Electron, Scanning Microscopy, Fluorescence Phosphatidylinositol Phosphates/metabolism Phosphoric Monoester Hydrolases/metabolism Phosphorylation Pinocytosis/physiology Protein Tyrosine Phosphatases, Non-Receptor/metabolism RNA Interference RNA, Small Interfering/genetics Reverse Transcriptase Polymerase Chain Reaction
Chemicals
DNA Primers Phosphatidylinositol Phosphates RNA, Small Interfering Phosphoric Monoester Hydrolases MTMR6 protein, human Protein Tyrosine Phosphatases, Non-Receptor phosphatidylinositol-3,4-bisphosphate 4-phosphatase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Maekawa Masashi
Department of Health Chemistry and Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Terasaka Shimpei
Mochizuki Yasuhiro
Kawai Katsuhisa
Ikeda Yuka
Araki Nobukazu
Skolnik Edward Y
Taguchi Tomohiko
Arai Hiroyuki
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1311029111
Published
2014-03-18
Epub
2014-00-03
Pages
E978-87
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3964036
Subset
IM
Grants
NIAID NIH HHS · R01 AI080583 · United States
NIGMS NIH HHS · R01 GM099873 · United States
NIAID NIH HHS · R01AI080583 · United States
External Links
PubMed source DOI: 10.1073/pnas.1311029111 PMC Full Text View journal details
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