CD19
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Location (UCSC) | Chr 16: 28.93 – 28.94 Mb | Chr 7: 126.01 – 126.01 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
B-lymphocyte antigen CD19, also known as CD19 molecule (
Structure
In humans, CD19 is encoded by the 7.41 kilobase CD19 gene located on the short arm of chromosome 16.[11][12] It contains at least fifteen exons, four that encode extracellular domain and nine that encode cytoplasmic domains, with a total of 556 amino acids.[12] Experiments show that there are multiple mRNA transcripts; however, only two have been isolated in vivo.[11]
CD19 is a 95 kd Type I transmembrane glycoprotein in the immunoglobulin superfamily (IgSF) with two extracellular C2-set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species.[11][13][14][15] The extracellular C2-type Ig-like domains are divided by a potential disulfide linked non-Ig-like domain and N-linked carbohydrate addition sites.[14][16] The cytoplasmic tail contains at least nine tyrosine residues near the C-terminus.[11][14] Within these residues, Y391, Y482, and Y513 have been shown to be essential to the biological functions of CD19.[17] Phenylalanine substitution for tyrosine at Y482 and Y513 leads to the inhibition of phosphorylation at the other tyrosines.[11][18]
Expression
CD19 is widely expressed during all phases of B cell development until terminal differentiation into plasma cells. During B cell
Function
Role in development & survival
Decisions to live,
BCR-independent
Paired box transcription factor 5 (PAX5) plays a major role in B cell differentiation from pro B cell to mature B cell, the point at which the expression of non-B-lineage genes is permanently blocked.[23][24][25] Part of B cell differentiation is controlling c-MYC protein stability and steady-state levels through CD19, which acts as a PAX5 target and downstream effector of the PI3K-AKT-GSK3β axis. CD19 signaling, independent of BCR functions, increases c-MYC protein stability. Using a loss of function approach, researchers found reduced MYC levels in B cells of CD19 knockdown mice.[23] CD19 signaling involves the recruitment and activation of phosphoinositide 3-kinase (PI3K) and later downstream, the activation of protein kinase B (Akt). The Akt-GSK3β axis is necessary for MYC activation by CD19 in BCR-negative cells, with higher levels of Akt activation corresponding to higher levels of MYC.[23][26] CD19 is a crucial BCR-independent regulator of MYC-driven neoplastic growth in B cells since the CD19-MYC axis promotes cell expansion in vitro and in vivo.[23][26]
CD19/CD21 complex
On the cell surface, CD19 is the dominant signaling component of a multimolecular complex including CD21 (CR2, a complement receptor), TAPA-1 (a tetraspanin membrane protein), and CD225.[11][23] The CD19/CD21 complex arises from C3d binding to CD21; however, CD19 does not require CD21 for signal transduction. CD81, attached to CD19, is a part of the tetraspanin web, acts as a chaperone protein, and provides docking sites for molecules in various different signal transduction pathways.[11]
BCR-dependent
While colligated with the BCR, the CD19/CD21 complex bound to the antigen-complement complex can decrease the threshold for B cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation.[27] Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase signaling and by extension, MHC class II mediated signaling.[11]
Activated spleen tyrosine kinase (
Interactions
CD19 has been shown to
In disease
Autoimmunity & immunodeficiency
Mutations in CD19 are associated with severe immunodeficiency syndromes characterized by diminished antibody production.[28][29] Additionally, mutations in CD21 and CD81 can also underlie primary immunodeficiency due to their role in the CD19/CD21 complex formation.[30] These mutations can lead to hypogammaglobulinaemia as a result of poor response to antigen and defective immunological memory.[31] Researchers found changes in the constitution of B lymphocyte population and reduced amounts of switched memory B cells with high terminal differentiation potential in patients with Down Syndrome.[32] CD19 has also been implicated in autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and may be a useful treatment target.[13][16][33]
Mouse model research shows that CD19 deficiency can lead to hyporesponsiveness to transmembrane signals and weak
Cancer
Since CD19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell - notably
CD19-targeted therapies based on T cells that express CD19-specific chimeric antigen receptors (
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000177455 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030724 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: CD19 CD19 molecule".
- S2CID 22081793.
- ^ )
- ^ PMID 8528044.
- PMID 8551226.
- S2CID 45937555.
- ^ PMID 23210908.
- ^ S2CID 7182703.
- ^ PMID 23281743.
- ^ PMID 15934172.
- S2CID 22081793.
- ^ S2CID 6143992.
- S2CID 45145420.
- ^ S2CID 35818699.
- PMID 12496385.
- PMID 10651223.
- ^ S2CID 4337673.
- ^ PMID 7542548.
- ^ PMID 22546857.
- S2CID 28197010.
- PMID 14500810.
- ^ PMID 22826319.
- ^ PMID 26478008.
- PMID 2479707.
- PMID 16672701.
- PMID 25472482.
- PMID 25159464.
- S2CID 19318246.
- S2CID 9666705.
- S2CID 43750896.
- PMID 21830940.
- PMID 29245005.
- ^ Clinical trial number NCT01493453 for "A Phase I Study of CD19 Specific T Cells in CD19 Positive Malignancy" at ClinicalTrials.gov
- PMID 28057672.
Further reading
- Goldsby, Richard A., Kindt, Thomas J., Osborne, Barbara A. (2006). Kuby Immunology. San Francisco: W. H. Freeman. ISBN 978-0-7167-8590-3.
- Ishikawa H, Tsuyama N, Mahmoud MS, Fujii R, Abroun S, Liu S, Li FJ, Kawano MM (March 2002). "CD19 expression and growth inhibition of tumours in human multiple myeloma". Leukemia & Lymphoma. 43 (3): 613–6. S2CID 20765908.
- Zhou LJ, Ord DC, Omori SA, Tedder TF (1992). "Structure of the genes encoding the CD19 antigen of human and mouse B lymphocytes". Immunogenetics. 35 (2): 102–11. S2CID 7182703.
- Carter RH, Fearon DT (April 1992). "CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes". Science. 256 (5053): 105–7. PMID 1373518.
- Kozmik Z, Wang S, Dörfler P, Adams B, Busslinger M (June 1992). "The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP". Molecular and Cellular Biology. 12 (6): 2662–72. PMID 1375324.
- Bradbury LE, Kansas GS, Levy S, Evans RL, Tedder TF (November 1992). "The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules". Journal of Immunology. 149 (9): 2841–50. S2CID 23655762.
- Matsumoto AK, Kopicky-Burd J, Carter RH, Tuveson DA, Tedder TF, Fearon DT (January 1991). "Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19". The Journal of Experimental Medicine. 173 (1): 55–64. PMID 1702139.
- Zhou LJ, Ord DC, Hughes AL, Tedder TF (August 1991). "Structure and domain organization of the CD19 antigen of human, mouse, and guinea pig B lymphocytes. Conservation of the extensive cytoplasmic domain". Journal of Immunology. 147 (4): 1424–32. S2CID 1167309.
- Stamenkovic I, Seed B (September 1988). "CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail". The Journal of Experimental Medicine. 168 (3): 1205–10. PMID 2459292.
- Ord DC, Edelhoff S, Dushkin H, Zhou LJ, Beier DR, Disteche C, Tedder TF (1994). "CD19 maps to a region of conservation between human chromosome 16 and mouse chromosome 7". Immunogenetics. 39 (5): 322–8. S2CID 9336224.
- Weng WK, Jarvis L, LeBien TW (December 1994). "Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors". The Journal of Biological Chemistry. 269 (51): 32514–21. PMID 7528218.
- Myers DE, Jun X, Waddick KG, Forsyth C, Chelstrom LM, Gunther RL, Tumer NE, Bolen J, Uckun FM (October 1995). "Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9575–9. PMID 7568175.
- Chalupny NJ, Aruffo A, Esselstyn JM, Chan PY, Bajorath J, Blake J, Gilliland LK, Ledbetter JA, Tepper MA (October 1995). "Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD19 through their src homology 2 domains". European Journal of Immunology. 25 (10): 2978–84. S2CID 9310907.
- Tuscano JM, Engel P, Tedder TF, Agarwal A, Kehrl JH (June 1996). "Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22". European Journal of Immunology. 26 (6): 1246–52. S2CID 29471624.
- Carter RH, Doody GM, Bolen JB, Fearon DT (April 1997). "Membrane IgM-induced tyrosine phosphorylation of CD19 requires a CD19 domain that mediates association with components of the B cell antigen receptor complex". Journal of Immunology. 158 (7): 3062–9. S2CID 20717278.
- Husson H, Mograbi B, Schmid-Antomarchi H, Fischer S, Rossi B (May 1997). "CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2". Oncogene. 14 (19): 2331–8. S2CID 967748.
- Khine AA, Firtel M, Lingwood CA (August 1998). "CD77-dependent retrograde transport of CD19 to the nuclear membrane: functional relationship between CD77 and CD19 during germinal center B-cell apoptosis". Journal of Cellular Physiology. 176 (2): 281–92. S2CID 10051140.
- Thunberg U, Gidlöf C, Bånghagen M, Sällström JF, Sundström C, Tötterman T (1998). "HpaII polymerase chain reaction restriction fragment length polymorphism in the human CD19 gene on 16p11". Human Heredity. 48 (4): 230–1. S2CID 32699676.
- Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E (November 1998). "CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82". The Journal of Biological Chemistry. 273 (46): 30537–43. PMID 9804823.
- Buhl AM, Cambier JC (April 1999). "Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase". Journal of Immunology. 162 (8): 4438–46. S2CID 23542951.
External links
- Mouse CD Antigen Chart
- Human CD Antigen Chart
- Human CD19 genome location and CD19 gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.