A TMEM16F point mutation causes an absence of canine platelet TMEM16F and ineffective activation and death‐induced phospholipid scrambling

Brooks, Marjory B.; Catalfamo, James L.; MacNguyen, Richard; Tim, David; Fancher, Samantha; McCardle, James A.

doi:10.1111/jth.13157

Cited by 34 publications

(25 citation statements)

References 62 publications

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“…This correlates with other groups' observation of a marked decrease in death-and activation-induced phospholipid scrambling [16,28,29]. Recently beneficial effects of anion channel blockade have been shown in a rat model of ischemia reperfusion [30].…”

Section: Discussionsupporting

confidence: 63%

TMEM16F Regulates Baseline Phosphatidylserine Exposure and Cell Viability in Human Embryonic Kidney Cells

Schenk

Schulze

Henke

et al. 2016

Cell Physiol Biochem

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Background / Aims: TMEM16F is a transmembrane protein from a conserved family of Ca²⁺-activated proteins, which is highly expressed in several tissues. TMEM16F confers phospholipid scramblase activity and Ca²⁺-activated electrolyte channel activity. Potentially thereby, TMEM16F is involved in cell cycle control and apoptotic signaling. The present study evaluated the role of TMEM16F on cell proliferation and viability in Human Embryonic Kidney cells. Methods: An inducible knockdown of TMEM16F was generated and markers of apoptosis and proliferation were assessed via flow cytometry, western blotting and MTT uptake assay under different conditions. Results: TMEM16F knockdown resulted in attenuated growth of HEK293 cells. This observation correlated with an increased phosphatidylserine exposure and a decreased fraction of viable cells. Interestingly, the cells were not sensitized to Staurosporine- induced cell death. Western blot analyses displayed a parallel activation of pro- and antiapoptotic signaling pathways: Caspase 3 cleavage and Cyclin D1 abundance were simultaneously increased. Furthermore, knockdown of TMEM16F led to activation of AKT signaling. Conclusion: TMEM16F modifies viability of Human Embryonic Kidney cells via its function as a phospholipid scramblase and activation of AKT signaling pathways.

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Section: Discussionsupporting

confidence: 63%

TMEM16F Regulates Baseline Phosphatidylserine Exposure and Cell Viability in Human Embryonic Kidney Cells

Schenk

Schulze

Henke

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

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“…TMEM16F knockout mice reliably recapitulate the blood coagulation deficiencies observed in Scott patients (16,18). Furthermore, dogs with a hereditary bleeding disorder similar to Scott syndrome also exhibit mutations in the TMEM16F gene leading to loss of protein function (19). In addition to TMEM16F, five other members of the mammalian TMEM16 family have been attributed with phospholipid scrambling activity: TMEM16C, TMEM16D, TMEM16E, TMEM16G, and TMEM16J (20,21).…”

mentioning

confidence: 94%

Chemically induced vesiculation as a platform for studying TMEM16F activity

Han

Bethel

et al. 2019

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

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Calcium-activated phospholipid scramblase mediates the energy-independent bidirectional translocation of lipids across the bilayer, leading to transient or, in the case of apoptotic scrambling, sustained collapse of membrane asymmetry. Cells lacking TMEM16F-dependent lipid scrambling activity are deficient in generation of extracellular vesicles (EVs) that shed from the plasma membrane in a Ca2+-dependent manner, namely microvesicles. We have adapted chemical induction of giant plasma membrane vesicles (GPMVs), which require both TMEM16F-dependent phospholipid scrambling and calcium influx, as a kinetic assay to investigate the mechanism of TMEM16F activity. Using the GPMV assay, we identify and characterize both inactivating and activating mutants that elucidate the mechanism for TMEM16F activation and facilitate further investigation of TMEM16F-mediated lipid translocation and its role in extracellular vesiculation.

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“…The puzzle was solved in 2010 when the Nagata lab discovered that ANO6 is essential for Ca 2+ -dependent PLS (Ca 2+ -PLS) (16). Mutations in ANO6 are linked to a congenital bleeding disorder stemming from perturbed Ca 2+ -PLS in both humans (Scott Syndrome) (16) and dogs (17). Disruption of Ano6 in mouse phenocopies Scott Syndrome and perturbs Ca 2+ -PLS in cells isolated from these animals (16, 18–20).…”

Section: Introductionmentioning

confidence: 99%

Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles

Whitlock

Hartzell

2017

Annu. Rev. Physiol.

153

159

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Anoctamin/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca2+-activated Cl− channels, most ANO paralogs are Ca2+-dependent phospholipid scramblases that serve as channels that facilitate the movement (“scrambling”) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences. In particular, phosphatidylserine exposed on the external leaflet of the plasma membrane functions as a ligand for receptors vital for cell-cell communication. A major consequence of Ca2+-dependent scrambling is the release of extracellular vesicles that function as intercellular messengers by delivering signaling proteins and non-coding RNAs to alter target cell function. We discuss the physiological implications of Ca2+-dependent phospholipid scrambling, the extracellular vesicles associated with this activity, and the roles of ANOs in these processes.

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A TMEM16F point mutation causes an absence of canine platelet TMEM16F and ineffective activation and death‐induced phospholipid scrambling

Abstract: To cite this article: Brooks MB, Catalfamo JL, MacNguyen R, Tim D, Fancher S, McCardle JA. A TMEM16F point mutation causes an absence of canine platelet TMEM16F and ineffective activation and death-induced phospholipid scrambling. J Thromb Haemost 2015; 13: 2240-52.

Cited by 34 publications

References 62 publications

TMEM16F Regulates Baseline Phosphatidylserine Exposure and Cell Viability in Human Embryonic Kidney Cells

TMEM16F Regulates Baseline Phosphatidylserine Exposure and Cell Viability in Human Embryonic Kidney Cells

Chemically induced vesiculation as a platform for studying TMEM16F activity

Anoctamins/TMEM16 Proteins: Chloride Channels Flirting with Lipids and Extracellular Vesicles

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