Disease relevance of PLSCR1

• Co-immunoprecipitation analysis showed that both proteins form a protein complex at an endogenous expression level in the human neuroblastoma SH-SY5Ycells, and the dileucine residue of the BACE tail is also revealed to be essential for the physical interaction with PLSCR1 in vitro and in vivo [1].
• Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia [2].
• To study the potential contribution of cellular PLSCR1 to the antiproliferative and tumor-suppressive activities of IFN, PLSCR1 cDNA was stably expressed in the human ovarian cancer cell line HEY1B, and the growth of these cells was compared with matched vector transfected controls both in vitro and in vivo [3].
• Accordingly, human cells in which PLSCR1 expression was decreased with short interfering RNA were rendered relatively insensitive to the antiviral activity of IFNs, resulting in higher titers of vesicular stomatitis virus (VSV) and encephalomyocarditis virus [4].
• Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor [5].

High impact information on PLSCR1

• In patients with Scott syndrome, a congenital bleeding disorder related to defective expression of membrane coagulant activity, circulating blood cells show decreased cell surface exposure of phosphatidylserine at elevated cytosolic [Ca2+], implying an underlying defect or deficiency of PL scramblase [6].
• To gain insight into the molecular basis of this disorder, we compared PL scramblase in Scott erythrocyte membranes to those of normal controls [6].
• The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans [5].
• The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors [5].
• For instance, several novel ISGs were identified that are implicated in apoptosis (including RAP46/Bag-1, phospholipid scramblase, and hypoxia inducible factor-1alpha) [7].

Biological context of PLSCR1

• The influence of PKCdelta on IFN-mediated induction of PLSCR1 was dependent upon the phosphorylation of STAT1 at Ser-727 [8].
• We now report evidence that upon EGF stimulation, PLSCR1 is phosphorylated by c-Src, within the tandem repeat sequence 68VYNQPVYNQP77 [9].
• In this report, we investigate the potential role of PLSCR1 in leukemic cell differentiation [10].
• Although phospholipid scramblase 1 (PLSCR1) was originally identified based on its capacity to promote transbilayer movement of membrane phospholipids, subsequent studies also provided evidence for its role in cell proliferation, maturation, and apoptosis [10].
• Analysis of 5' flanking genomic sequence in reporter constructs showed that transcriptional control of PLSCR1 was entirely regulated by a single IFN-stimulated response element located in the first exon [11].

Anatomical context of PLSCR1

• These data suggest that in addition to its role at the plasma membrane, effects of PLSCR1 on cell proliferative and maturational responses may also relate to alterations in expression of cellular IP3 receptors [12].
• Consistent with the potential role of PLSCR1 in growth factor signaling pathways, granulocyte precursors derived from mice deficient in PLSCR1 show impaired proliferation and maturation under cytokine stimulation [9].
• In cultured cells, BACE and PLSCR1 were colocalized in the Golgi area and in endosomal compartments, whereas they were co-redistributed in late endosome-derived multivesicular bodies when treated with U18666A, suggesting that both proteins share a common trafficking pathway in cells [1].
• ATRA- and phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation is accompanied by increased PLSCR1 expression, whereas only a slight or no elevation of PLSCR1 expression is observed in U937 cells differentiated with dimethyl sulfoxide (DMSO), sodium butyrate, or vitamin D3 [10].
• A similar induction of PLSCR1 by IFN-alpha2a was also observed in a variety of other human tumor cell lines as well as in human umbilical vein endothelial cells [11].

Associations of PLSCR1 with chemical compounds

• The expression of PLSCR1 protein is also known to be markedly increased in response to IFN and to some differentiation inducing agents such as all-trans retinoic acid, but the precise mechanisms of this response remain to be investigated [8].
• In this study, we show that the protein kinase Cdelta (PKCdelta)-specific inhibitor rottlerin and the dominant negative mutant of PKCdelta significantly antagonized IFN-induced PLSCR1 expression [8].
• Moreover, we present in vivo evidence that the critical lysine at position P2, which is essential in other known NLS sequences, is dispensable in PLSCR1 NLS [13].
• The cisplatin-induced phosphorylation of PLSCR1 was inhibited by STI571 and was not observed in Abl-/- fibroblasts [14].
• Phospholipid flip-flop and phospholipid scramblase 1 (PLSCR1) co-localize to uropod rafts in formylated Met-Leu-Phe-stimulated neutrophils [15].

Physical interactions of PLSCR1

• We have conducted a search for additional onzin-interacting proteins and identified phospholipid scramblase 1 (PLSCR1), an endofacial membrane protein, which is proposed to mediate the bidirectional movement of plasma membrane phospholipids during proliferation and apoptosis [16].

Regulatory relationships of PLSCR1

• Finally, decreasing PLSCR1 expression with small interfering RNA inhibits ATRA/PMA-induced differentiation [10].

Other interactions of PLSCR1

• In conclusion, our results suggest that the induction of PLSCR1 transcription through STAT1 depends upon sequential activation of PKCdelta and JNK [8].
• Coinciding with phosphorylation, there was a transient increase in physical association of PLSCR1 with both the EGF receptor and the adapter protein Shc, as determined by immunoprecipitation and Western blotting [17].
• Cell stimulation with EGF transiently elevated Tyr-phosphorylation of PLSCR1, peaking at 5 min [17].
• PLSCR1 contains multiple proline-rich motifs resembling Src homology 3 (SH3) domain-binding sites [14].
• These findings demonstrate a functional interdependence between onzin and PLSCR1 [16].

Analytical, diagnostic and therapeutic context of PLSCR1

• Consistent with this interpretation, Western blotting revealed neither ubiquitination nor proteolysis of PLSCR1 under these conditions, whereas the ubiquitination and degradation of the EGF receptor were readily confirmed [17].
• Using antibodies to the carboxyl-terminal domain of PLSCR1, its presence in the plasma membranes of non-permeabilized neutrophils was confirmed by flow cytometry [15].
• Release of PLSCR1 from the nucleus was only observed after treatment of cells with both detergent and an elevated NaCl concentration, or following DNase treatment of the nucleus, suggesting ionic interactions of PLSCR1 with a nuclear component bound to genomic DNA or directly with genomic DNA [18].
• This PL scramblase activity co-eluted through multiple chromatographic steps with a single polypeptide of approximately 37 kDa, which was purified to apparent homogeneity as resolved by silver staining [19].
• Molecular cloning of human plasma membrane phospholipid scramblase. A protein mediating transbilayer movement of plasma membrane phospholipids [20].

References