@article{a77f19511930401cac041893731363ad,
title = "Reverse fountain flow of phosphatidylinositol-3,4-bisphosphate polarizes migrating cells",
abstract = "The ability of cells to polarize and move toward external stimuli plays a crucial role in development, as well as in normal and pathological physiology. Migrating cells maintain dynamic complementary distributions of Ras activity and of the phospholipid phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). Here, we show that lagging-edge component PI(3,4)P2 also localizes to retracting leading-edge protrusions and nascent macropinosomes, even in the absence of phosphatidylinositol 3,4,5-trisphosphate (PIP3). Once internalized, macropinosomes break up into smaller PI(3,4)P2-enriched vesicles, which fuse with the plasma membrane at the rear of the cell. Subsequently, the phosphoinositide diffuses toward the front of the cell, where it is degraded. Computational modeling confirms that this cycle gives rise to stable back-to-front gradient. These results uncover a surprising “reverse-fountain flow” of PI(3,4)P2 that regulates polarity.",
keywords = "cell migration, excitability, membrane flow, neutrophils, refractory period",
author = "Xiaoguang Li and Pal, {Dhiman Sankar} and Debojyoti Biswas and Iglesias, {Pablo A.} and Devreotes, {Peter N.}",
note = "Funding Information: The authors would like to thank all members of the Devreotes and Iglesias labs for helpful suggestions for this work. We thank the Johns Hopkins University Microscope Facility for confocal microscopy. We thank Dr. Carolyn Machamer, Dr. Geraldine Seydoux, Dr. Erin Goley, Dr. Shigeki Watanabe, and Dr. Doug Robinson for helpful suggestions. We thank Jane Borleis for providing PI3K1−2− cells. We thank Dr. Masahiro Ueda lab for PTEN-Halo and CAR1-KikGR constructs. We thank Dr. Stephen Desiderio Lab for RFP-LifeAct construct. We thank Dr. Gerald R.V. Hammond and Brady D. Goulden for providing cPHx3TAPP1 construct. We thank Dr. Miho Iijima for generating and providing RacH- cells. We thank Dr. Orion Weiner lab for providing HL-60 cell line. This work was supported by This work was supported by National Institutes of Health grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052, DARPA HR0011-16-C-0139, as well as NIH Grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility). Funding Information: The authors would like to thank all members of the Devreotes and Iglesias labs for helpful suggestions for this work. We thank the Johns Hopkins University Microscope Facility for confocal microscopy. We thank Dr. Carolyn Machamer, Dr. Geraldine Seydoux, Dr. Erin Goley, Dr. Shigeki Watanabe, and Dr. Doug Robinson for helpful suggestions. We thank Jane Borleis for providing cells. We thank Dr. Masahiro Ueda lab for PTEN‐Halo and CAR1‐KikGR constructs. We thank Dr. Stephen Desiderio Lab for RFP‐LifeAct construct. We thank Dr. Gerald R.V. Hammond and Brady D. Goulden for providing cPHx3 construct. We thank Dr. Miho Iijima for generating and providing cells. We thank Dr. Orion Weiner lab for providing HL‐60 cell line. This work was supported by This work was supported by National Institutes of Health grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052, DARPA HR0011‐16‐C‐0139, as well as NIH Grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility). PI3K1 − 2 − TAPP1 RacH‐ Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2021",
month = feb,
day = "15",
doi = "10.15252/embj.2020105094",
language = "English (US)",
volume = "40",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "4",
}