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Gene Review

CD46  -  CD46 molecule, complement regulatory protein

Homo sapiens

Synonyms: AHUS2, MCP, MGC26544, MIC10, Membrane cofactor protein, ...
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Disease relevance of CD46


Psychiatry related information on CD46

  • The molecular complex involving CD46 may confer high MV permissiveness leading to immune modulation in Mphi [6].
  • The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001) [7].
  • Normal controls (NC) (n = 15), patients with panic disorder (PD) (n = 13) and patients with major depression (MD) (n = 17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo [8].
  • However, correlations were found between MCP and neuroticism and extroversion scores from a personality inventory and physical variables [9].
  • However, the observed anxiogenic properties of MCPP suggest that additional studies of the role of serotonin systems in the pathophysiology of human anxiety disorders are indicated [10].

High impact information on CD46


Chemical compound and disease context of CD46


Biological context of CD46

  • Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype [16].
  • Here, we report that infection of human epithelial cells by piliated Neisseria gonorrhoeae (GC) leads to rapid tyrosine phosphorylation of CD46 [3].
  • CD46 mutants with truncated cytoplasmic tails fail to support bacterial adhesion (Källström et al., 2001), suggesting that this region of the molecule also plays an important role in infection [3].
  • We examined the activities of recombinant variants of CD46, including different isoforms as well as engineered truncations and molecular chimeras with decay-accelerating factor, a related protein in the family of regulators of complement activation (RCA) [13].
  • Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46 [17].

Anatomical context of CD46

  • Furthermore, infected CD46+ cells produced syncytia and viral proteins [1].
  • These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype [16].
  • We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46 [12].
  • Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites [12].
  • However, cross-linking of CD46 at the cell surface, by either multivalent antibody or by measles virus, induces pseudopodia that engulf the ligand in a process similar to macropinocytosis, and leads to the degradation of cell surface CD46 [17].

Associations of CD46 with chemical compounds

  • The pilus binds CD46, a complement-regulatory glycoprotein present on nucleated human cells (Källström et al., 1997) [3].
  • Studies with wild-type and mutant tail fusion constructs demonstrate that Src kinase phosphorylates tyrosine 354 in the Cyt2 isoform of the CD46 cytoplasmic tail [3].
  • These data, together with cross-linking experiments showing the existence in living cells of CD46/integrin complexes, suggest that CD46 associates directly with beta1 integrins and indirectly with tetraspans [18].
  • Multiple molecular weight isoforms of membrane bound CD46 are produced by alternative splicing of the CD46 mRNA in an area coding for the serine/threonine/proline-rich region or for the cytoplasmic tail [19].
  • Exposure of the cells to hydrogen peroxide (H2O2) or their detachment from the pericellular matrix increased the shedding of soluble CD46 [19].

Physical interactions of CD46


Regulatory relationships of CD46


Other interactions of CD46

  • Thus, CD46, CD55, and CD59 expression on pretreatment tumor cells, or their susceptibility to in vitro complement-mediated killing, does not predict clinical outcome after rituximab treatment [5].
  • The effect of CD46 on IL-10 secretion did not require additional costimuli like anti-CD28 antibodies or phorbol esters [21].
  • However, CD46 cross-linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti-CD46 antibodies did not significantly alter TCR/CD3 activation [21].
  • A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro [25].
  • Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium [22].

Analytical, diagnostic and therapeutic context of CD46

  • Ad3 colocalized with cell surface CD46 in both rodent and human cells at the light and electron microscopy levels [26].
  • We have examined the relative mRNA expression of the complement (C) regulatory proteins CD59, CD55 and CD46 in RNA isolated from 50 primary breast cancer specimens using a semiquantitative RT-PCR approach [27].
  • A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation [28].
  • We observed that tumor cells liberated intact 60-65 kDa forms of CD46 into the cell culture medium on the surface of vesicles with a diameter of 200 nm [19].
  • Transgenic pigs expressed high levels of CD46 in all tissues, especially vascular endothelium, with stable expression through three generations that was readily monitored by flow cytometry of transgenic peripheral blood mononuclear cells (PBMC) [29].


  1. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Dörig, R.E., Marcil, A., Chopra, A., Richardson, C.D. Cell (1993) [Pubmed]
  2. CD46 is a cellular receptor for human herpesvirus 6. Santoro, F., Kennedy, P.E., Locatelli, G., Malnati, M.S., Berger, E.A., Lusso, P. Cell (1999) [Pubmed]
  3. CD46 is phosphorylated at tyrosine 354 upon infection of epithelial cells by Neisseria gonorrhoeae. Lee, S.W., Bonnah, R.A., Higashi, D.L., Atkinson, J.P., Milgram, S.L., So, M. J. Cell Biol. (2002) [Pubmed]
  4. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Richards, A., Kemp, E.J., Liszewski, M.K., Goodship, J.A., Lampe, A.K., Decorte, R., Müslümanoğlu, M.H., Kavukcu, S., Filler, G., Pirson, Y., Wen, L.S., Atkinson, J.P., Goodship, T.H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  5. Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma. Weng, W.K., Levy, R. Blood (2001) [Pubmed]
  6. Molecular assembly of CD46 with CD9, alpha3-beta1 integrin and protein tyrosine phosphatase SHP-1 in human macrophages through differentiation by GM-CSF. Kurita-Taniguchi, M., Hazeki, K., Murabayashi, N., Fukui, A., Tsuji, S., Matsumoto, M., Toyoshima, K., Seya, T. Mol. Immunol. (2002) [Pubmed]
  7. The MCPP challenge test in schizophrenia: hormonal and behavioral responses. Iqbal, N., Asnis, G.M., Wetzler, S., Kahn, R.S., Kay, S.R., van Praag, H.M. Biol. Psychiatry (1991) [Pubmed]
  8. Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder. Kahn, R.S., Asnis, G.M., Wetzler, S., van Praag, H.M. Psychopharmacology (Berl.) (1988) [Pubmed]
  9. Relationship between blood meperidine concentrations and analgesic response: a preliminary report. Austin, K.L., Stapleton, J.V., Mather, L.E. Anesthesiology (1980) [Pubmed]
  10. Serotonin function in anxiety. II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects. Charney, D.S., Woods, S.W., Goodman, W.K., Heninger, G.R. Psychopharmacology (Berl.) (1987) [Pubmed]
  11. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Liszewski, M.K., Post, T.W., Atkinson, J.P. Annu. Rev. Immunol. (1991) [Pubmed]
  12. CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells. Elward, K., Griffiths, M., Mizuno, M., Harris, C.L., Neal, J.W., Morgan, B.P., Gasque, P. J. Biol. Chem. (2005) [Pubmed]
  13. Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function. Greenstone, H.L., Santoro, F., Lusso, P., Berger, E.A. J. Biol. Chem. (2002) [Pubmed]
  14. Characterisation of the complement-regulatory proteins decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46) on a human colonic adenocarcinoma cell line. Bjørge, L., Jensen, T.S., Matre, R. Cancer Immunol. Immunother. (1996) [Pubmed]
  15. Intracellular processing of human herpesvirus 6 glycoproteins Q1 and Q2 into tetrameric complexes expressed on the viral envelope. Akkapaiboon, P., Mori, Y., Sadaoka, T., Yonemoto, S., Yamanishi, K. J. Virol. (2004) [Pubmed]
  16. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Kemper, C., Chan, A.C., Green, J.M., Brett, K.A., Murphy, K.M., Atkinson, J.P. Nature (2003) [Pubmed]
  17. Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis. Crimeen-Irwin, B., Ellis, S., Christiansen, D., Ludford-Menting, M.J., Milland, J., Lanteri, M., Loveland, B.E., Gerlier, D., Russell, S.M. J. Biol. Chem. (2003) [Pubmed]
  18. CD46 (membrane cofactor protein) associates with multiple beta1 integrins and tetraspans. Lozahic, S., Christiansen, D., Manié, S., Gerlier, D., Billard, M., Boucheix, C., Rubinstein, E. Eur. J. Immunol. (2000) [Pubmed]
  19. Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble form. Hakulinen, J., Junnikkala, S., Sorsa, T., Meri, S. Eur. J. Immunol. (2004) [Pubmed]
  20. Engagement of CD46 and alpha5beta1 integrin by group A streptococci is required for efficient invasion of epithelial cells. Rezcallah, M.S., Hodges, K., Gill, D.B., Atkinson, J.P., Wang, B., Cleary, P.P. Cell. Microbiol. (2005) [Pubmed]
  21. CD46-mediated costimulation induces a Th1-biased response and enhances early TCR/CD3 signaling in human CD4+ T lymphocytes. Sánchez, A., Feito, M.J., Rojo, J.M. Eur. J. Immunol. (2004) [Pubmed]
  22. Expression of CD59, a complement regulator protein and a second ligand of the CD2 molecule, and CD46 in normal and neoplastic colorectal epithelium. Koretz, K., Brüderlein, S., Henne, C., Möller, P. Br. J. Cancer (1993) [Pubmed]
  23. Lack of effect of different cytokines on expression of membrane-bound regulators of complement activity on human uveal melanoma cells. Blom, D.J., Goslings, W.R., De Waard-Siebinga, I., Luyten, G.P., Claas, F.H., Gorter, A., Jager, M.J. J. Interferon Cytokine Res. (1997) [Pubmed]
  24. CD46/CD3 costimulation induces morphological changes of human T cells and activation of Vav, Rac, and extracellular signal-regulated kinase mitogen-activated protein kinase. Zaffran, Y., Destaing, O., Roux, A., Ory, S., Nheu, T., Jurdic, P., Rabourdin-Combe, C., Astier, A.L. J. Immunol. (2001) [Pubmed]
  25. A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro. Christiansen, D., Milland, J., Thorley, B.R., McKenzie, I.F., Loveland, B.E. Eur. J. Immunol. (1996) [Pubmed]
  26. The human membrane cofactor CD46 is a receptor for species B adenovirus serotype 3. Sirena, D., Lilienfeld, B., Eisenhut, M., Kälin, S., Boucke, K., Beerli, R.R., Vogt, L., Ruedl, C., Bachmann, M.F., Greber, U.F., Hemmi, S. J. Virol. (2004) [Pubmed]
  27. Analysis of the level of mRNA expression of the membrane regulators of complement, CD59, CD55 and CD46, in breast cancer. Rushmere, N.K., Knowlden, J.M., Gee, J.M., Harper, M.E., Robertson, J.F., Morgan, B.P., Nicholson, R.I. Int. J. Cancer (2004) [Pubmed]
  28. A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation. Kroshus, T.J., Salerno, C.T., Yeh, C.G., Higgins, P.J., Bolman, R.M., Dalmasso, A.P. Transplantation (2000) [Pubmed]
  29. Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons. Loveland, B.E., Milland, J., Kyriakou, P., Thorley, B.R., Christiansen, D., Lanteri, M.B., Regensburg, M., Duffield, M., French, A.J., Williams, L., Baker, L., Brandon, M.R., Xing, P.X., Kahn, D., McKenzie, I.F. Xenotransplantation (2004) [Pubmed]
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