Roles and regulation of phospholipid scramblases

Abstract

Phospholipid scramblase activity is involved in the collapse of phospholipid (PL) asymmetry at the plasma membrane leading to externalization of phosphatidylserine. This activity is crucial for initiation of the blood coagulation cascade and for recognition/elimination of apoptotic cells by macrophages. Efforts to identify gene products associated with this activity led to the characterization of PL scramblase (PLSCR) and XKR family members which contribute to phosphatidylserine exposure in response to apoptotic stimuli. Meanwhile, TMEM16 family members were identified to externalize phosphatidylserine in response to elevated calcium in Scott syndrome platelets, which is critical for activation of the coagulation cascade. Herein, we report their mechanisms of gene regulation, molecular functions independent of their scrambling activity, and their potential roles in pathogenic conditions.

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

“…Apoptosis goes along with phospholipid scrambling and PtdSer exposition [14] and TMEM16F, among others, functions as a phospholipid scramblase [4,26]. Thus Annexin V-FITC staining was employed to test if TMEM16F KD altered the amount of PtdSer exposed on the external leaflet of the plasma membrane.…”

“…Phospholipid scrambling by TMEM16F can occur during apoptosis or upon cell activation [7,14,15]. This effect is essential during platelet activation and bone mineralization by osteoblasts [1,[16][17][18][19].…”

Use of Annexin V based Sperm Selection in Assisted Reproduction

“…The lipid bilayer shows a bent shape and contains a concave region in the annexin-membrane interaction interface, which supports the idea that ANX V could disturb the stability of lipids and bend membranes [66]. Cell injury leads to redistribution of lipids within the plasma membrane resulting in surface exposure of PS and phosphatidylethanolamine (PE) [67] and phospholipid scramblase activity produces a collapse of phospholipid asymmetry with externalization of PS [68]. The physiological functions known for externalized PS are: (1) control of the hemostatic balance, since several pro-coagulant as well as anticoagulant reactions require PS-containing lipid surfaces [69], and (2) mediating recognition and clearance of apoptotic cells by phagocytic cells, to prevent release of the inflammatory cell content upon cell lysis [70].…”

Natural products against hematological malignancies and identification of their targets

“…Moreover, the induction of PLSCR1 transcription depends upon sequential activation of protein kinase C delta (PKC), c-Jun N-terminal kinases, and the phosphorylation of STAT1 at Ser-727 [99]. PLSCR1 was also shown to interact with several protein kinases including c-Abl, c-Src, PKC and onzin, suggesting a role of PLSCR1 in cell signaling [100][101][102]. Employinging an inducible PLSCR1-expressing myeloid leukemia U937 cell line, we showed that inducible PLSCR1 expression arrests the proliferation at the G 1 phase and induces granulocyte-like differentiation with increased sensitivity to etoposide-induced apoptosis of the genetically engineered cells [103].…”