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

Masashi Maekawa, Shimpei Terasaka, Yasuhiro Mochizuki, Katsuhisa Kawai, Yuka Ikeda, Nobukazu Araki, Edward Y. Skolnik, Tomohiko Taguchi, Hiroyuki Arai

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81 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)E978-E987
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
Publication statusPublished - 2014 Mar 18
Externally publishedYes

ASJC Scopus subject areas

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