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Gene Review

PLSCR1  -  phospholipid scramblase 1

Homo sapiens

Synonyms: Ca(2+)-dependent phospholipid scramblase 1, Erythrocyte phospholipid scramblase, MMTRA1B, MmTRA1b, PL scramblase 1, ...
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Disease relevance of PLSCR1


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


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


Regulatory relationships of PLSCR1

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

Other interactions of PLSCR1


Analytical, diagnostic and therapeutic context of PLSCR1


  1. Identification of phospholipid scramblase 1 as a novel interacting molecule with beta -secretase (beta -site amyloid precursor protein (APP) cleaving enzyme (BACE)). Kametaka, S., Shibata, M., Moroe, K., Kanamori, S., Ohsawa, Y., Waguri, S., Sims, P.J., Emoto, K., Umeda, M., Uchiyama, Y. J. Biol. Chem. (2003) [Pubmed]
  2. Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia. Rami, A., Sims, J., Botez, G., Winckler, J. Neurochem. Int. (2003) [Pubmed]
  3. Suppression of ovarian carcinoma cell growth in vivo by the interferon-inducible plasma membrane protein, phospholipid scramblase 1. Silverman, R.H., Halloum, A., Zhou, A., Dong, B., Al-Zoghaibi, F., Kushner, D., Zhou, Q., Zhao, J., Wiedmer, T., Sims, P.J. Cancer Res. (2002) [Pubmed]
  4. Phospholipid scramblase 1 potentiates the antiviral activity of interferon. Dong, B., Zhou, Q., Zhao, J., Zhou, A., Harty, R.N., Bose, S., Banerjee, A., Slee, R., Guenther, J., Williams, B.R., Wiedmer, T., Sims, P.J., Silverman, R.H. J. Virol. (2004) [Pubmed]
  5. Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3). Wiedmer, T., Zhao, J., Li, L., Zhou, Q., Hevener, A., Olefsky, J.M., Curtiss, L.K., Sims, P.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Scott syndrome erythrocytes contain a membrane protein capable of mediating Ca2+-dependent transbilayer migration of membrane phospholipids. Stout, J.G., Bassé, F., Luhm, R.A., Weiss, H.J., Wiedmer, T., Sims, P.J. J. Clin. Invest. (1997) [Pubmed]
  7. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Der, S.D., Zhou, A., Williams, B.R., Silverman, R.H. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Interferon-alpha-induced expression of phospholipid scramblase 1 through STAT1 requires the sequential activation of protein kinase Cdelta and JNK. Zhao, K.W., Li, D., Zhao, Q., Huang, Y., Silverman, R.H., Sims, P.J., Chen, G.Q. J. Biol. Chem. (2005) [Pubmed]
  9. Plasma membrane phospholipid scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor. Nanjundan, M., Sun, J., Zhao, J., Zhou, Q., Sims, P.J., Wiedmer, T. J. Biol. Chem. (2003) [Pubmed]
  10. Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation. Zhao, K.W., Li, X., Zhao, Q., Huang, Y., Li, D., Peng, Z.G., Shen, W.Z., Zhao, J., Zhou, Q., Chen, Z., Sims, P.J., Wiedmer, T., Chen, G.Q. Blood (2004) [Pubmed]
  11. Transcriptional control of the human plasma membrane phospholipid scramblase 1 gene is mediated by interferon-alpha. Zhou, Q., Zhao, J., Al-Zoghaibi, F., Zhou, A., Wiedmer, T., Silverman, R.H., Sims, P.J. Blood (2000) [Pubmed]
  12. Phospholipid scramblase 1 binds to the promoter region of the inositol 1,4,5-triphosphate receptor type 1 gene to enhance its expression. Zhou, Q., Ben-Efraim, I., Bigcas, J.L., Junqueira, D., Wiedmer, T., Sims, P.J. J. Biol. Chem. (2005) [Pubmed]
  13. Phospholipid scramblase 1 contains a nonclassical nuclear localization signal with unique binding site in importin alpha. Chen, M.H., Ben-Efraim, I., Mitrousis, G., Walker-Kopp, N., Sims, P.J., Cingolani, G. J. Biol. Chem. (2005) [Pubmed]
  14. c-Abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Sun, J., Zhao, J., Schwartz, M.A., Wang, J.Y., Wiedmer, T., Sims, P.J. J. Biol. Chem. (2001) [Pubmed]
  15. Phospholipid flip-flop and phospholipid scramblase 1 (PLSCR1) co-localize to uropod rafts in formylated Met-Leu-Phe-stimulated neutrophils. Frasch, S.C., Henson, P.M., Nagaosa, K., Fessler, M.B., Borregaard, N., Bratton, D.L. J. Biol. Chem. (2004) [Pubmed]
  16. The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase 1. Li, Y., Rogulski, K., Zhou, Q., Sims, P.J., Prochownik, E.V. Mol. Cell. Biol. (2006) [Pubmed]
  17. Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor. Sun, J., Nanjundan, M., Pike, L.J., Wiedmer, T., Sims, P.J. Biochemistry (2002) [Pubmed]
  18. Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated pathway and interacts with DNA. Ben-Efraim, I., Zhou, Q., Wiedmer, T., Gerace, L., Sims, P.J. Biochemistry (2004) [Pubmed]
  19. Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid. Bassé, F., Stout, J.G., Sims, P.J., Wiedmer, T. J. Biol. Chem. (1996) [Pubmed]
  20. Molecular cloning of human plasma membrane phospholipid scramblase. A protein mediating transbilayer movement of plasma membrane phospholipids. Zhou, Q., Zhao, J., Stout, J.G., Luhm, R.A., Wiedmer, T., Sims, P.J. J. Biol. Chem. (1997) [Pubmed]
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