TY - JOUR
T1 - Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis
AU - Maekawa, Masashi
AU - Terasaka, Shimpei
AU - Mochizuki, Yasuhiro
AU - Kawai, Katsuhisa
AU - Ikeda, Yuka
AU - Araki, Nobukazu
AU - Skolnik, Edward Y.
AU - Taguchi, Tomohiko
AU - Arai, Hiroyuki
PY - 2014/3/18
Y1 - 2014/3/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84896503356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896503356&partnerID=8YFLogxK
U2 - 10.1073/pnas.1311029111
DO - 10.1073/pnas.1311029111
M3 - Article
C2 - 24591580
AN - SCOPUS:84896503356
SN - 0027-8424
VL - 111
SP - E978-E987
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -