Phosphoinositide metabolism during membrane ruffling and macropinosome formation in EGF-stimulated A431 cells

Araki, Nobuhito; Egami, Youhei; Watanabe, Yasuo; Hatae, Tanenori

doi:10.1016/j.yexcr.2007.02.012

Cited by 110 publications

(139 citation statements)

References 58 publications

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“…PI(3,4,5)P 3 , which was probed by Akt1-PH (45), appeared in membrane ruffles 3 min after EGF stimulation and dissipated mostly by 10 min in control cells (Fig. 5A), as reported previously (18). In contrast, PI(3,4,5)P 3 lingered in membrane ruffles even 10 min after EGF stimulation in cells depleted of SHIP2, indicating that SHIP2 mediates PI(3,4,5)P 3 dephosphorylation in membrane ruffles.…”

Section: Dynamics Of Phosphoinositides In Membrane Ruffles Duringsupporting

confidence: 86%

“…As reported (18,33), time-lapse video microscopy of A431 cells stimulated with EGF revealed that prominent phase-dark ruffles originated from the cell periphery and moved along the dorsal cell surface toward the center of the cells (Movie S1). During this process, some ruffles subsequently close, resulting in the formation of phase-bright macropinosomes (Fig.…”

Section: Resultssupporting

confidence: 67%

“…3C), indicating that the PHG domains are necessary and sufficient for targeting of MTMR6/ MTMR9 to membrane ruffles. Recent studies have shown that PI(3,4,5)P 3 and PI(3,4)P 2 are transiently generated in membrane ruffles and dissipated during macropinocytosis (17)(18)(19)(20). Moreover, PI3K and 5-phosphatase SHIP2 have been shown to be required for macropinocytosis through phosphorylation of PI(4,5)P 2 and dephosphorylation of PI(3,4,5)P 3 , respectively (Fig.…”

Section: Mtmr6 and Mtmr9 Are Recruited To Membrane Ruffles Upon Egfmentioning

confidence: 97%

“…The dynamic nature of phosphoinositides during macropinocytosis has been described. In EGF-stimulated A431 cells, the PI(4,5)P 2 level increases in membrane ruffles, reaches its maximum before circular ruffle formation, and rapidly falls afterward (18). In contrast, the PI (3,4,5)P 3 level increases in circular ruffles and peaks at the beginning of circular ruffle fusion.…”

mentioning

confidence: 90%

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

Maekawa

Shimpei²,

Mochizuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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109

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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)P 3 and PI(3,4) P 2 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)P 2 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)P 3 → PI(3,4)P 2 → PI(3)P → PI controls macropinocytosis through specific effectors of the intermediate phosphoinositides.

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Section: Dynamics Of Phosphoinositides In Membrane Ruffles Duringsupporting

confidence: 86%

Section: Resultssupporting

confidence: 67%

Section: Mtmr6 and Mtmr9 Are Recruited To Membrane Ruffles Upon Egfmentioning

confidence: 97%

mentioning

confidence: 90%

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

Maekawa

Shimpei²,

Mochizuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

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“…This suggests that C12-200 particles may be internalized through a macropinocytosis mechanism (26,27). One of the hallmarks of such an uptake pathway is membrane ruffling and actin rearrangement (28), which was observed in HeLa cells within 15 min of the application of the particles (Fig. 6B).…”

Section: Resultsmentioning

confidence: 87%

Lipid-like materials for low-dose, in vivo gene silencing

Love

Mahon

Levins

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

794

793

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Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.

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Inositol, neural tube closure and the prevention of neural tube defects

Greene

Leung

Copp

2017

Birth Defects Research

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Susceptibility to neural tube defects (NTDs), such as anencephaly and spina bifida is influenced by genetic and environmental factors including maternal nutrition. Maternal periconceptional supplementation with folic acid significantly reduces the risk of an NTD‐affected pregnancy, but does not prevent all NTDs, and “folic acid non‐responsive” NTDs continue to occur. Similarly, among mouse models of NTDs, some are responsive to folic acid but others are not.Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate‐deficiency induced NTD model. NTDs also occur in mice lacking expression of certain inositol kinases. Inositol‐containing phospholipids (phosphoinositides) and soluble inositol phosphates mediate a range of functions, including intracellular signaling, interaction with cytoskeletal proteins, and regulation of membrane identity in trafficking and cell division. Myo‐inositol has been trialed in humans for a range of conditions and appears safe for use in human pregnancy. In pilot studies in Italy and the United Kingdom, women took inositol together with folic acid preconceptionally, after one or more previous NTD‐affected pregnancies. In nonrandomized cohorts and a randomized double‐blind study in the United Kingdom, no recurrent NTDs were observed among 52 pregnancies reported to date.Larger‐scale fully powered trials are needed to determine whether supplementation with inositol and folic acid would more effectively prevent NTDs than folic acid alone. Birth Defects Research 109:68–80, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.

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Phosphoinositide metabolism during membrane ruffling and macropinosome formation in EGF-stimulated A431 cells

Cited by 110 publications

References 58 publications

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

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

Lipid-like materials for low-dose, in vivo gene silencing

Inositol, neural tube closure and the prevention of neural tube defects

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