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Gene Review

MS4A1  -  membrane-spanning 4-domains, subfamily A,...

Homo sapiens

Synonyms: B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, B1, Bp35, CD20, ...


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Disease relevance of MS4A1

  • Transfection of CD20 cDNA and subsequent expression of CD20 in nonlymphoid cells (human K562 erythroleukemia cells and mouse NIH-3T3 fibroblasts) also induced the expression of an identical transmembrane Ca2+ conductance [1].
  • Despite the clinical success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about its mechanism of action [2].

    It has been shown that CD20 is required for B Cell Receptor signalling in B cells, and rituximab primarily eliminates the malignant B cells that have a high potential for activation of this fundamental pathway   . This might partially explain the great clinical success of anti-CD20 monoclonal antibodies in the therapy of B cell malignancies.

  • CD20 expression on T cells may be seen in either normal, reactive, or neoplastic processes [3].
  • CD20 antigen expression in B-chronic lymphocytic leukemia (B-CLL) is at significantly lower levels than in non-Hodgkins lymphoma, which may affect the degree of anti-CD20 antibody binding [4].
  • GM-CSF does not increase CD20 antigen expression on chronic lymphocytic leukemia lymphocytes [4].
  • The mean fluorescence intensity of CD20 on fresh lymphoma cells was significantly lower for the C-terminal deletion mutation [3.26; 95% confidence interval (95% CI), 0.09-6.89] compared with wild type (30.8; 95% CI, 22.4-39.2; P < 0.05) [5].

Psychiatry related information on MS4A1


High impact information on MS4A1

  • The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B [7].
  • We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse [8].
  • The numbers of lymphocytes positive for T3, T4, T8, and B1 declined progressively during treatment [9].
  • Assuming then that the rates of translation of A5 and B1 DHFR mRNAs in the wheat germ cell-free system are the same, our results show that a major part of the high DHFR levels observed in A5 cells is due to the presence of elevated quantities of DHFR mRNA [10].
  • Transcription, processing and nuclear transport of a B1 Alu RNA species complementary to an intron of the murine alpha-fetoprotein gene [11].

Chemical compound and disease context of MS4A1

  • The present study was designed to investigate relationships between the efficacy of IDEC-C2B8 and expression of CD20, presence of complement, and effects of differently acting chemotherapeutic agents used in lymphoma treatment (doxorubicin, mitoxantrone, cladribine, bendamustine) [12].
  • CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insoluble membrane rafts [13].
  • In vitro, L6-CD but not 1F5-CD selectively metabolized 5-FCyt to 5-FU on H2981 human lung adenocarcinoma cells because of the presence and absence of cell surface L6 and CD20 antigens, respectively [14].
  • To identify promising agents for clinical testing, we assessed the in vitro cytotoxicity of combinations of (131)I-anti-B1 (anti-CD20) antibody and 8 chemotherapeutic agents using 2 human CD20-expressing lymphoma cell lines and 2 corroborative assays, the thiazolyl tetrazolium bromide (MTT) and the Trypan blue dye exclusion assays [15].
  • Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA), a monoclonal antibody against CD20, was combined with dose-adjusted EPOCH (infusional etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) chemotherapy and tested in 38 untreated or relapsed poor-prognosis aggressive lymphomas [16].

Biological context of MS4A1


Anatomical context of MS4A1

  • CD20 is an antigen expressed on normal and malignant human B cells that is thought to function as a receptor during B cell activation [17].
  • The diminished expression appeared to be unrelated to B-cell (CD20) and T-cell (CD2) expression [20].
  • COS cells transfected with either CD20 clone express an immunoreactive protein of 33 kD [21].
  • Transfection of human T and mouse pre-B lymphoblastoid cell lines with CD20 cDNA and subsequent stable expression of CD20 specifically increased transmembrane Ca2+ conductance [1].
  • Whole-cell patch clamp and fluorescence microscopy measurements of plasma membrane ionic conductance and cytosolic-free Ca2+ activity, respectively, were used to directly examine CD20 function [1].

Associations of MS4A1 with chemical compounds

  • CD20 lacks an NH2-terminal signal peptide and contains a highly charged COOH-terminal domain [17].
  • The mechanism underlying antibody-induced association of CD20 with Triton-resistant rafts was investigated and found not to require cellular ATP, kinase activity, actin polymerization, or antibody cross-linking but was dependent on the epitope recognized [22].
  • The B cell Ag receptor (BCR) and CD20, a putative calcium channel, inducibly associate with cholesterol-dependent membrane microdomains known as lipid rafts [23].
  • Pretreatment with methyl-beta-cyclodextrin, which we have previously shown to enhance receptor-mediated calcium mobilization, did not prevent colocalization of the BCR and CD20, but slowed their dissociation [23].
  • The cytoplasmic domains of CD20 contain multiple serine and threonine residues, of which at least two are followed by acidic sequences typical of substrate sites favored by casein kinase II [19].

Enzymatic interactions of MS4A1

  • CD20 was strongly phosphorylated on resting B cells after CDw40 stimulation, suggesting that CD20 may be functionally regulated by a protein kinase(s) [17].
  • Tryptic mapping of CD20 isolated from intact cells treated with insulin showed increased phosphorylation on peptides having similar migration to those phosphorylated by casein kinase II in vitro [19].

Regulatory relationships of MS4A1

  • Monoclonal antibodies (mAbs) to either Bp35 or Bp50 deliver positive signals to B cells that stimulate their transition through the cell cycle. mAb to Bp35, like anti-immunoglobulin antibodies, functions principally to activate resting B cells to become competent to enter the G1 phase of the cell cycle [24].
  • Our studies indicate that transcriptional synergy mediated by activation of both Egr-1 and NF-kappa B may have important ramifications in T cell development by upregulating NF-kappa B1 gene expression [25].

Other interactions of MS4A1

  • Triggering of neoplastic B cells via surface IgM and the cell surface antigens CD20 and CDw40. Responses differ from normal blood B cells and are restricted to certain morphologic subsets [26].
  • These exosomes also expressed the B cell marker CD20, and the complement inhibitory protein CD59 [27].
  • The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p < 0.001 [28].
  • The anti-CD20 (Bp35) MAb IF5 can deliver a strong activation signal to resting normal B cells, and the anti-CDw40 (Bp50) MAb G28-5 can promote activated G1 B cells to enter S phase [26].
  • The leukemic cells were negative for surface CD3, CD2, and CD7 and strongly positive for CD20 [29].

Analytical, diagnostic and therapeutic context of MS4A1

  • Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains [17].
  • Biochemical cross-linking of cell-surface molecules with subsequent immunoprecipitation analysis of CD20 suggests that CD20 may be present as a multimeric oligomer within the membrane, as occurs with several known membrane channels [1].
  • Differences in complement recruitment could not be explained by the level of mAb binding or isotype but did correlate with the redistribution of CD20 in the cell membrane following mAb ligation [2].
  • Southern blot analysis revealed that CD20 mRNA was transcribed from a single-copy gene [30].
  • CD20 was distributed in a punctate pattern on the cell surface as visualized by fluorescence imaging and was also localized to microvilli by electron microscopy [22].


  1. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. Bubien, J.K., Zhou, L.J., Bell, P.D., Frizzell, R.A., Tedder, T.F. J. Cell Biol. (1993) [Pubmed]
  2. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Cragg, M.S., Morgan, S.M., Chan, H.T., Morgan, B.P., Filatov, A.V., Johnson, P.W., French, R.R., Glennie, M.J. Blood (2003) [Pubmed]
  3. CD20 (pan-B cell antigen) expression on bone marrow-derived T cells. Algino, K.M., Thomason, R.W., King, D.E., Montiel, M.M., Craig, F.E. Am. J. Clin. Pathol. (1996) [Pubmed]
  4. GM-CSF does not increase CD20 antigen expression on chronic lymphocytic leukemia lymphocytes. Yağci, M., Akar, I., Sucak, G.T., Haznedar, R. Leuk. Res. (2005) [Pubmed]
  5. Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin's lymphoma. Terui, Y., Mishima, Y., Sugimura, N., Kojima, K., Sakurai, T., Mishima, Y., Kuniyoshi, R., Taniyama, A., Yokoyama, M., Sakajiri, S., Takeuchi, K., Watanabe, C., Takahashi, S., Ito, Y., Hatake, K. Clin. Cancer Res. (2009) [Pubmed]
  6. Substance abuse vulnerability and D2 receptor genes. Uhl, G., Blum, K., Noble, E., Smith, S. Trends Neurosci. (1993) [Pubmed]
  7. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Palombella, V.J., Rando, O.J., Goldberg, A.L., Maniatis, T. Cell (1994) [Pubmed]
  8. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. Press, O.W., Eary, J.F., Appelbaum, F.R., Martin, P.J., Badger, C.C., Nelp, W.B., Glenn, S., Butchko, G., Fisher, D., Porter, B. N. Engl. J. Med. (1993) [Pubmed]
  9. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. McCune, W.J., Golbus, J., Zeldes, W., Bohlke, P., Dunne, R., Fox, D.A. N. Engl. J. Med. (1988) [Pubmed]
  10. Elevated dihydrofolate reductase messenger RNA levels in methotrexate-resistant BHK cells. Chang, S.E., Littlefield, J.W. Cell (1976) [Pubmed]
  11. Transcription, processing and nuclear transport of a B1 Alu RNA species complementary to an intron of the murine alpha-fetoprotein gene. Adeniyi-Jones, S., Zasloff, M. Nature (1985) [Pubmed]
  12. Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases. Chow, K.U., Sommerlad, W.D., Boehrer, S., Schneider, B., Seipelt, G., Rummel, M.J., Hoelzer, D., Mitrou, P.S., Weidmann, E. Haematologica (2002) [Pubmed]
  13. CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insoluble membrane rafts. Chan, H.T., Hughes, D., French, R.R., Tutt, A.L., Walshe, C.A., Teeling, J.L., Glennie, M.J., Cragg, M.S. Cancer Res. (2003) [Pubmed]
  14. Intratumoral conversion of 5-fluorocytosine to 5-fluorouracil by monoclonal antibody-cytosine deaminase conjugates: noninvasive detection of prodrug activation by magnetic resonance spectroscopy and spectroscopic imaging. Aboagye, E.O., Artemov, D., Senter, P.D., Bhujwalla, Z.M. Cancer Res. (1998) [Pubmed]
  15. Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas. Johnson, T.A., Press, O.W. Int. J. Cancer (2000) [Pubmed]
  16. The role of rituximab and chemotherapy in aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. Wilson, W.H., Gutierrez, M., O'Connor, P., Frankel, S., Jaffe, E., Chabner, B.A., Grossbard, M.L. Semin. Oncol. (2002) [Pubmed]
  17. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. Einfeld, D.A., Brown, J.P., Valentine, M.A., Clark, E.A., Ledbetter, J.A. EMBO J. (1988) [Pubmed]
  18. Isolation and structure of a cDNA encoding the B1 (CD20) cell-surface antigen of human B lymphocytes. Tedder, T.F., Streuli, M., Schlossman, S.F., Saito, H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  19. Insulin regulates serine/threonine phosphorylation in activated human B lymphocytes. Valentine, M.A., Licciardi, K.A., Clark, E.A., Krebs, E.G., Meier, K.E. J. Immunol. (1993) [Pubmed]
  20. Surgical and molecular approaches to the sentinel lymph nodes. Essner, R., Kojima, M. Ann. Surg. Oncol. (2001) [Pubmed]
  21. Analysis of two cDNA clones encoding the B lymphocyte antigen CD20 (B1, Bp35), a type III integral membrane protein. Stamenkovic, I., Seed, B. J. Exp. Med. (1988) [Pubmed]
  22. The CD20 calcium channel is localized to microvilli and constitutively associated with membrane rafts: antibody binding increases the affinity of the association through an epitope-dependent cross-linking-independent mechanism. Li, H., Ayer, L.M., Polyak, M.J., Mutch, C.M., Petrie, R.J., Gauthier, L., Shariat, N., Hendzel, M.J., Shaw, A.R., Patel, K.D., Deans, J.P. J. Biol. Chem. (2004) [Pubmed]
  23. Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts. Petrie, R.J., Deans, J.P. J. Immunol. (2002) [Pubmed]
  24. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Clark, E.A., Ledbetter, J.A. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  25. Involvement of Egr-1/RelA synergy in distinguishing T cell activation from tumor necrosis factor-alpha-induced NF-kappa B1 transcription. Cogswell, P.C., Mayo, M.W., Baldwin, A.S. J. Exp. Med. (1997) [Pubmed]
  26. Triggering of neoplastic B cells via surface IgM and the cell surface antigens CD20 and CDw40. Responses differ from normal blood B cells and are restricted to certain morphologic subsets. Beiske, K., Clark, E.A., Holte, H., Ledbetter, J.A., Smeland, E.B., Godal, T. Int. J. Cancer (1988) [Pubmed]
  27. Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. Clayton, A., Court, J., Navabi, H., Adams, M., Mason, M.D., Hobot, J.A., Newman, G.R., Jasani, B. J. Immunol. Methods (2001) [Pubmed]
  28. Infectious agents, inflammation, and growth factors: how do they interact in the progression or stabilization of mild human atherosclerotic lesions? G??is, J., Higuchi, M., Reis, M., Diament, J., Sousa, J., Ramires, J., Oliveira, S. Annals of vascular surgery (2006) [Pubmed]
  29. CD3-negative, CD20-positive T-cell prolymphocytic leukemia: case report and review of the literature. Tamayose, K., Sato, N., Ando, J., Sugimoto, K., Oshimi, K. Am. J. Hematol. (2002) [Pubmed]
  30. Structure of the gene encoding the human B lymphocyte differentiation antigen CD20 (B1). Tedder, T.F., Klejman, G., Schlossman, S.F., Saito, H. J. Immunol. (1989) [Pubmed]
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