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Gene Review

EPB41  -  erythrocyte membrane protein band 4.1

Homo sapiens

Synonyms: 4.1R, Band 4.1, E41P, EL1, EPB4.1, ...
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Disease relevance of EPB41


Psychiatry related information on EPB41


High impact information on EPB41

  • Indirect evidence suggests that the genetic defect in hereditary spherocytosis lies in the erythrocyte membrane skeleton, a submembranous meshwork of proteins (principally spectrin, actin, and protein 4.1) responsible for membrane shape and structural stability [7].
  • A genetic defect in the binding of protein 4.1 to spectrin in a kindred with hereditary spherocytosis [7].
  • We show that Crb controls localization of the adherens junction through its intracellular domain containing a putative binding site for a protein 4.1 superfamily protein (FERM) [8].
  • Spectrin, the most abundant component of this assembly, is an elongated and flexible molecule that, with potentiation by protein 4.1, is cross-linked at its ends by short actin filaments to form a lattice beneath the membrane [9].
  • Fractionally mobile integral proteins, such as band 3, and highly mobile receptors, such as CD59 as well as glycophorin C in protein 4.1-deficient cells, appeared to be squeezed out of areas dense in the underlying network and enriched in areas of network dilation [10].

Chemical compound and disease context of EPB41

  • Additionally, frozen tissue from nine ependymomas (four intracranial and five spinal) was obtained for Western blot analysis for merlin, 4.1B and 4.1R expression [3].
  • We here analyze the molecular basis of heterozygous 4.1(-) hereditary elliptocytosis, associated with protein 4.1 partial deficiency, in nine related French families. cDNA sequencing revealed a single codon deletion (AAA) resulting in a lysine residue deletion within the 10-kD binding domain, 3' of Motif I [11].
  • Erythrocyte membranes (ghosts) and membrane skeletons (submembranous reticula of spectrin, actin, and protein 4.1 prepared by extracting ghosts with Triton X-100) from 15 patients with hereditary elliptocytosis (HE) were elliptical, which indicates that the primary defect responsible for the abnormal shape of these cells resides in the skeleton [12].

Biological context of EPB41

  • The EPB41 and EPB41L3 genes from fish, bird, amphibian, and mammal genomes exhibit shared features including alternative first exons and differential splice acceptors in exon 2 [13].
  • The EPB41 (protein 4.1) genes epitomize the resourcefulness of the mammalian genome to encode a complex proteome from a small number of genes [14].
  • GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis [1].
  • Nineteen samples with 1p LOH (12 grade I; 7 grade II, WHO classification) and 20 samples without 1p LOH (18 grade I; 2 grade II) were also analyzed by means of real-time polymerase chain reaction to find abnormalities in EPB41 mRNA levels in meningioma [1].
  • Some patients with recessive HS have a mutation in the spectrin alpha-2 domain (S.L.M. et al., unpublished observations), and a few dominant HS patients have an unstable beta-spectrin that is easily oxidized, which damages the protein 4.1 binding site and weakens spectrin-actin interactions [15].

Anatomical context of EPB41

  • Identification of the binding interface involved in linkage of cytoskeletal protein 4.1 to the erythrocyte anion exchanger [16].
  • Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells [17].
  • These data suggest that the stability of 4.1R association with centrosomes requires an intact C-terminal end, either for a proper conformation of the protein, for a direct binding to an unknown centrosome-cytoskeletal network, or for both [18].
  • Furthermore, phosphorylation of these residues appears to be essential for the targeting of 4.1R to the spindle poles and for mitotic microtubule aster assembly in vitro [19].
  • Finally, we used siRNA inhibition to deplete 4.1R from HeLa cells and provide the first direct genetic evidence that 4.1R is required to efficiently focus mitotic spindle poles [19].

Associations of EPB41 with chemical compounds


Physical interactions of EPB41

  • A nonerythroid isoform of protein 4.1R interacts with the nuclear mitotic apparatus (NuMA) protein [25].
  • PIP(2) had no effect on 4.1R binding to p55 [20].
  • To evaluate the functional significance of protein 4.1R binding for subcellular localization of hDlg in vivo, we expressed full-length recombinant constructs of two naturally occurring isoforms of hDlg termed hDlg-I2 and hDlg-I3 [26].
  • Protein 4.1 interacts with TRPC4 and the membrane skeleton [27].
  • Protein 4.1R binding to eIF3-p44 suggests an interaction between the cytoskeletal network and the translation apparatus [28].

Enzymatic interactions of EPB41

  • Here, we show that protein 4.1 is phosphorylated on tyrosine by the epidermal growth factor receptor (EGFR) tyrosine kinase [22].
  • Protein 4.1 phosphorylated by casein kinase A and protein kinase C, but not cAMP-dependent protein kinase, exhibits a reduced binding to KI-extracted inside-out vesicles [29].

Regulatory relationships of EPB41


Other interactions of EPB41

  • The minimal sequence sufficient for this interaction has been mapped to the amino acids encoded by exons 20 and 21 of 4.1R and residues 1788-1810 of NuMA [25].
  • These findings led to the postulate that the coexpression at the spindle poles of 2 related proteins, 4.1R and 4.1G, might reflect a functional redundancy in mitotic cells [18].
  • Using a yeast two-hybrid system, we isolated a novel human centrosomal protein, CPAP (centrosomal P4.1-associated protein), which specifically interacts with the head domain of the 135-kDa protein 4.1R isoform (4.1R-135) [30].
  • Furthermore, GPC was more readily extracted by Titon X-100 from adenosine triphosphate (ATP)-depleted erythrocytes, implying that the GPC-4.1R interaction may be regulated by PIP(2) in situ [20].
  • The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion [31].

Analytical, diagnostic and therapeutic context of EPB41


  1. GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis. Piaskowski, S., Rieske, P., Szybka, M., Wozniak, K., Bednarek, A., Płuciennik, E., Jaskolski, D., Sikorska, B., Liberski, P.P. Cancer Genet. Cytogenet. (2005) [Pubmed]
  2. Molecular basis of red cell membrane disorders. Delaunay, J. Acta Haematol. (2002) [Pubmed]
  3. Alterations of protein 4.1 family members in ependymomas: a study of 84 cases. Rajaram, V., Gutmann, D.H., Prasad, S.K., Mansur, D.B., Perry, A. Mod. Pathol. (2005) [Pubmed]
  4. Membrane skeleton protein 4.1 in developing Xenopus: expression in postmitotic cells of the retina. Spencer, M., Giebelhaus, D.H., Kelly, G.M., Bicknell, J., Florio, S.K., Milam, A.H., Moon, R.T. Dev. Biol. (1990) [Pubmed]
  5. Loss of DAL-1, a protein 4.1-related tumor suppressor, is an important early event in the pathogenesis of meningiomas. Gutmann, D.H., Donahoe, J., Perry, A., Lemke, N., Gorse, K., Kittiniyom, K., Rempel, S.A., Gutierrez, J.A., Newsham, I.F. Hum. Mol. Genet. (2000) [Pubmed]
  6. Evidence for the association of protein 4.1 immunoreactive forms with neurofibrillary tangles in Alzheimer's disease brains. Sihag, R.K., Wang, L.W., Cataldo, A.M., Hamlin, M., Cohen, C.M., Nixon, R.A. Brain Res. (1994) [Pubmed]
  7. A genetic defect in the binding of protein 4.1 to spectrin in a kindred with hereditary spherocytosis. Wolfe, L.C., John, K.M., Falcone, J.C., Byrne, A.M., Lux, S.E. N. Engl. J. Med. (1982) [Pubmed]
  8. Drosophila Crumbs is a positional cue in photoreceptor adherens junctions and rhabdomeres. Izaddoost, S., Nam, S.C., Bhat, M.A., Bellen, H.J., Choi, K.W. Nature (2002) [Pubmed]
  9. Modulation of spectrin-actin assembly by erythrocyte adducin. Gardner, K., Bennett, V. Nature (1987) [Pubmed]
  10. Molecular maps of red cell deformation: hidden elasticity and in situ connectivity. Discher, D.E., Mohandas, N., Evans, E.A. Science (1994) [Pubmed]
  11. Protein 4.1 deficiency associated with an altered binding to the spectrin-actin complex of the red cell membrane skeleton. Lorenzo, F., Dalla Venezia, N., Morlé, L., Baklouti, F., Alloisio, N., Ducluzeau, M.T., Roda, L., Lefrançois, P., Delaunay, J. J. Clin. Invest. (1994) [Pubmed]
  12. Elliptical erythrocyte membrane skeletons and heat-sensitive spectrin in hereditary elliptocytosis. Tomaselli, M.B., John, K.M., Lux, S.E. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  13. Evolutionarily conserved coupling of transcription and alternative splicing in the EPB41 (protein 4.1R) and EPB41L3 (protein 4.1B) genes. Tan, J.S., Mohandas, N., Conboy, J.G. Genomics (2005) [Pubmed]
  14. Differential domain evolution and complex RNA processing in a family of paralogous EPB41 (protein 4.1) genes facilitate expression of diverse tissue-specific isoforms. Parra, M., Gee, S., Chan, N., Ryaboy, D., Dubchak, I., Mohandas, N., Gascard, P.D., Conboy, J.G. Genomics (2004) [Pubmed]
  15. Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8. Lux, S.E., Tse, W.T., Menninger, J.C., John, K.M., Harris, P., Shalev, O., Chilcote, R.R., Marchesi, S.L., Watkins, P.C., Bennett, V. Nature (1990) [Pubmed]
  16. Identification of the binding interface involved in linkage of cytoskeletal protein 4.1 to the erythrocyte anion exchanger. Jöns, T., Drenckhahn, D. EMBO J. (1992) [Pubmed]
  17. Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. Cohen, A.R., Woods, D.F., Marfatia, S.M., Walther, Z., Chishti, A.H., Anderson, J.M., Wood, D.F. J. Cell Biol. (1998) [Pubmed]
  18. A splicing alteration of 4.1R pre-mRNA generates 2 protein isoforms with distinct assembly to spindle poles in mitotic cells. Delhommeau, F., Vasseur-Godbillon, C., Leclerc, P., Schischmanoff, P.O., Croisille, L., Rince, P., Morinière, M., Benz, E.J., Tchernia, G., Tamagnini, G., Ribeiro, L., Delaunay, J., Baklouti, F. Blood (2002) [Pubmed]
  19. Mitotic regulation of protein 4.1R involves phosphorylation by cdc2 kinase. Huang, S.C., Liu, E.S., Chan, S.H., Munagala, I.D., Cho, H.T., Jagadeeswaran, R., Benz, E.J. Mol. Biol. Cell (2005) [Pubmed]
  20. Phosphatidylinositol-4,5-Biphosphate (PIP(2)) Differentially Regulates the Interaction of Human Erythrocyte Protein 4.1 (4.1R) with Membrane Proteins. An, X., Zhang, X., Debnath, G., Baines, A.J., Mohandas, N. Biochemistry (2006) [Pubmed]
  21. Regulation of protein 4.1R interactions with membrane proteins by Ca2+ and calmodulin. Nunomura, W., Takakuwa, Y. Front. Biosci. (2006) [Pubmed]
  22. Phosphorylation of protein 4.1 on tyrosine-418 modulates its function in vitro. Subrahmanyam, G., Bertics, P.J., Anderson, R.A. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  23. Glycophorin C content of human erythrocyte membrane is regulated by protein 4.1. Reid, M.E., Takakuwa, Y., Conboy, J., Tchernia, G., Mohandas, N. Blood (1990) [Pubmed]
  24. Plasmodium falciparum cysteine protease falcipain-2 cleaves erythrocyte membrane skeletal proteins at late stages of parasite development. Hanspal, M., Dua, M., Takakuwa, Y., Chishti, A.H., Mizuno, A. Blood (2002) [Pubmed]
  25. A nonerythroid isoform of protein 4.1R interacts with the nuclear mitotic apparatus (NuMA) protein. Mattagajasingh, S.N., Huang, S.C., Hartenstein, J.S., Snyder, M., Marchesi, V.T., Benz, E.J. J. Cell Biol. (1999) [Pubmed]
  26. Protein 4.1-mediated membrane targeting of human discs large in epithelial cells. Hanada, T., Takeuchi, A., Sondarva, G., Chishti, A.H. J. Biol. Chem. (2003) [Pubmed]
  27. Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4. Cioffi, D.L., Wu, S., Alexeyev, M., Goodman, S.R., Zhu, M.X., Stevens, T. Circ. Res. (2005) [Pubmed]
  28. Protein 4.1R binding to eIF3-p44 suggests an interaction between the cytoskeletal network and the translation apparatus. Hou, C.L., Tang, C., Roffler, S.R., Tang, T.K. Blood (2000) [Pubmed]
  29. Modulation of protein 4.1 binding to inside-out membrane vesicles by phosphorylation. Chao, T.S., Tao, M. Biochemistry (1991) [Pubmed]
  30. Protein 4.1 R-135 interacts with a novel centrosomal protein (CPAP) which is associated with the gamma-tubulin complex. Hung, L.Y., Tang, C.J., Tang, T.K. Mol. Cell. Biol. (2000) [Pubmed]
  31. The protein 4.1 tumor suppressor, DAL-1, impairs cell motility, but regulates proliferation in a cell-type-specific fashion. Gutmann, D.H., Hirbe, A.C., Huang , Z.Y., Haipek, C.A. Neurobiol. Dis. (2001) [Pubmed]
  32. Identification of a third Protein 4.1 tumor suppressor, Protein 4.1R, in meningioma pathogenesis. Robb, V.A., Li, W., Gascard, P., Perry, A., Mohandas, N., Gutmann, D.H. Neurobiol. Dis. (2003) [Pubmed]
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