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'''CD244''' ('''C'''luster of '''D'''ifferentiation 244), also named 2B4 or SLAMF4, is a type-I transmembrane protein belonging to the signaling lymphocytic activation molecule family of receptors (SLAMF) which are expressed in different types of hematopoietic cells<ref name=":0">{{Cite journal |last=Pahima |first=Hadas |last2=Puzzovio |first2=Pier Giorgio |last3=Levi-Schaffer |first3=Francesca |date=2019 |title=2B4 and CD48: A powerful couple of the immune system |url=https://linkinghub.elsevier.com/retrieve/pii/S1521661618305795 |journal=Clinical Immunology |language= |volume=204 |pages=64–68 |doi=10.1016/j.clim.2018.10.014}}</ref>. CD244 plays a role in the regulation of the immune system<ref name=":1">{{Cite journal |last=Sun |first=Lin |last2=Gang |first2=Xiaokun |last3=Li |first3=Zhuo |last4=Zhao |first4=Xue |last5=Zhou |first5=Tong |last6=Zhang |first6=Siwen |last7=Wang |first7=Guixia |date=2021 |title=Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases |url=https://www.frontiersin.org/articles/10.3389/fimmu.2021.648182/full |journal=Frontiers in Immunology |volume=12 |doi=10.3389/fimmu.2021.648182 |issn=1664-3224 |pmc=PMC8024546 |pmid=33841431}}</ref>. |
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'''CD244''' ('''C'''luster of '''D'''ifferentiation 244) is a human [[protein]] encoded by the {{gene|CD244}} [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CD244 CD244 molecule, natural killer cell receptor 2B4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=51744}}</ref> It is also known as Natural Killer Cell Receptor 2B4<ref>{{OMIM|605554}}</ref> |
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A ligand of CD244 is CD48 (SLAMF2). CD48 also belongs to the SLAMF, it does not have an intracellular domain and it is anchored to the plasma membrane by a GPI-anchor<ref name=":0" />. Only these two receptors from the SLAMF mediate heterophilic interactions<ref name=":2">{{Cite journal |last=van Driel |first=Boaz Job |last2=Liao |first2=Gongxian |last3=Engel |first3=Pablo |last4=Terhorst |first4=Cox |date=2016 |title=Responses to Microbial Challenges by SLAMF Receptors |url=http://journal.frontiersin.org/Article/10.3389/fimmu.2016.00004/abstract |journal=Frontiers in Immunology |volume=7 |doi=10.3389/fimmu.2016.00004 |issn=1664-3224 |pmc=PMC4718992 |pmid=26834746}}</ref><ref name=":1" />. |
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This gene encodes a cell surface receptor expressed on [[natural killer cells]] (NK cells) (and some T cells) mediating non-major histocompatibility complex (MHC) restricted killing. The interaction between NK-cell and target cells via this receptor is thought to modulate NK-cell cytolytic activity. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.<ref name="NCBI">{{cite web | title = CD244 molecule, natural killer cell receptor 2B4 ( Homo sapiens (human) ) | url = https://www.ncbi.nlm.nih.gov/gene/51744}}</ref> |
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CD244 can also be expressed on non-lymphocytes such as eosinophils, mast cells and dendritic cells.<ref>{{cite journal | pmid = 25643613 | doi=10.1038/icb.2014.124 | volume=93 | issue=6 | title=CD244 is expressed on dendritic cells and regulates their functions | year=2015 | journal=Immunol Cell Biol | pages=581–90 | vauthors=Georgoudaki AM, Khodabandeh S, Puiac S, Persson CM, Larsson MK, Lind M, Hammarfjord O, Nabatti TH, Wallin RP, Yrlid U, Rhen M, Kumar V, Chambers BJ | s2cid=34400690 }}</ref> |
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== Gene == |
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The receptor CD244 is encoded by the {{gene|CD244}} [[gene]]<ref name=":3">{{Cite web |title=CD244 CD244 molecule [Homo sapiens (human)] - Gene - NCBI |url=https://www.ncbi.nlm.nih.gov/gene/51744 |access-date= |website=www.ncbi.nlm.nih.gov}}</ref> located on the long arm of human chromosome 1<ref name=":2" />. Alternatively spliced transcript variants encoding different isoforms have been found for this gene<ref name=":3" /><ref name=":4">{{Cite journal |last=Agresta |first=Laura |last2=Hoebe |first2=Kasper H. N. |last3=Janssen |first3=Edith M. |date=2018 |title=The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment |url=https://www.frontiersin.org/articles/10.3389/fimmu.2018.02809 |journal=Frontiers in Immunology |volume=9 |doi=10.3389/fimmu.2018.02809 |issn=1664-3224 |pmc=PMC6279924 |pmid=30546369}}</ref>. CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells<ref name=":2" /><ref name=":5">{{Cite journal |last=Buller |first=Casey W. |last2=Mathew |first2=Porunelloor A. |last3=Mathew |first3=Stephen O. |date=2020 |title=Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer |url=https://www.mdpi.com/2072-6694/12/7/1755 |journal=Cancers |language= |volume=12 |issue=7 |pages=1755 |doi=10.3390/cancers12071755 |issn=2072-6694 |pmc=PMC7409338 |pmid=32630303}}</ref>. |
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== Structure == |
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The receptor is composed of intracellular, transmembrane, and extracellular domains. The intracellular domain contains four intracellular tyrosine-based switch motives (ITSMs) and interacts with SH2 domain-containing proteins which are involved in the signaling and determine whether it will be activating or inhibitory<ref name=":4" /><ref name=":0" />. The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain<ref name=":5" /><ref name=":0" />. |
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== Function == |
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CD244 can function as an activating or inhibitory receptor. The expression and availability of an adaptor protein SAP determine whether the signal is activating or inhibitory<ref name=":4" />. The inhibitory signal is mediated by binding of phosphatases SHP1, SHP2, SHIP-1 or the kinase CsK on the third ITSM<ref name=":0" />. Activating signaling is associated with the adaptor protein SAP<ref name=":4" />. SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the kinase Fyn and that enhances downstream signaling<ref>{{Cite journal |last=Dragovich |first=Matthew A. |last2=Mor |first2=Adam |date=2018 |title=The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases |url=https://www.sciencedirect.com/science/article/pii/S1568997218301071 |journal=Autoimmunity Reviews |language= |volume=17 |issue=7 |pages=674–682 |doi=10.1016/j.autrev.2018.01.018 |issn=1568-9972 |pmc=PMC6508580 |pmid=29729453}}</ref>. Binding of EAT2 is associated with both the activating and the inhibitory signal<ref name=":4" />. |
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CD244 is expressed in all types of NK cells<ref name=":4" />, and it activates their cytotoxicity and IFNγ production<ref name=":4" /><ref name=":0" />. It is also expressed in a subset of effector and effector memory CD8+ T cells<ref name=":4" /> where the activating signaling via CD244 enhances their proliferation and cytotoxic effect<ref name=":0" />. |
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== Role of CD244 in viral infections == |
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NK cells and CD8+ T cells play a crucial role in antiviral immunity. The activating signaling via CD244 leads to an enhancement of their cytolytic activity that they use for killing infected cells<ref name=":1" />. The expression of CD244 is increased but the expression of SAP is decreased during some chronic viral infections, such as HIV, HBV and HCV, and that is associated with the inhibitory signal and the exhaustion od CD8+ T cells<ref name=":1" /><ref name=":4" />. |
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==See also== |
==See also== |
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Revision as of 23:10, 29 June 2023
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CD244, 2B4, NAIL, NKR2B4, Nmrk, SLAMF4, CD244 molecule | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605554; MGI: 109294; HomoloGene: 9493; GeneCards: CD244; OMA:CD244 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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CD244 (Cluster of Differentiation 244), also named 2B4 or SLAMF4, is a type-I transmembrane protein belonging to the signaling lymphocytic activation molecule family of receptors (SLAMF) which are expressed in different types of hematopoietic cells[5]. CD244 plays a role in the regulation of the immune system[6].
A ligand of CD244 is CD48 (SLAMF2). CD48 also belongs to the SLAMF, it does not have an intracellular domain and it is anchored to the plasma membrane by a GPI-anchor[5]. Only these two receptors from the SLAMF mediate heterophilic interactions[7][6].
Gene
The receptor CD244 is encoded by the CD244 gene[8] located on the long arm of human chromosome 1[7]. Alternatively spliced transcript variants encoding different isoforms have been found for this gene[8][9]. CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells[7][10].
Structure
The receptor is composed of intracellular, transmembrane, and extracellular domains. The intracellular domain contains four intracellular tyrosine-based switch motives (ITSMs) and interacts with SH2 domain-containing proteins which are involved in the signaling and determine whether it will be activating or inhibitory[9][5]. The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain[10][5].
Function
CD244 can function as an activating or inhibitory receptor. The expression and availability of an adaptor protein SAP determine whether the signal is activating or inhibitory[9]. The inhibitory signal is mediated by binding of phosphatases SHP1, SHP2, SHIP-1 or the kinase CsK on the third ITSM[5]. Activating signaling is associated with the adaptor protein SAP[9]. SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the kinase Fyn and that enhances downstream signaling[11]. Binding of EAT2 is associated with both the activating and the inhibitory signal[9].
CD244 is expressed in all types of NK cells[9], and it activates their cytotoxicity and IFNγ production[9][5]. It is also expressed in a subset of effector and effector memory CD8+ T cells[9] where the activating signaling via CD244 enhances their proliferation and cytotoxic effect[5].
Role of CD244 in viral infections
NK cells and CD8+ T cells play a crucial role in antiviral immunity. The activating signaling via CD244 leads to an enhancement of their cytolytic activity that they use for killing infected cells[6]. The expression of CD244 is increased but the expression of SAP is decreased during some chronic viral infections, such as HIV, HBV and HCV, and that is associated with the inhibitory signal and the exhaustion od CD8+ T cells[6][9].
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000122223 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000004709 – 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.
- ^ a b c d e f g Pahima, Hadas; Puzzovio, Pier Giorgio; Levi-Schaffer, Francesca (2019). "2B4 and CD48: A powerful couple of the immune system". Clinical Immunology. 204: 64–68. doi:10.1016/j.clim.2018.10.014.
- ^ a b c d Sun, Lin; Gang, Xiaokun; Li, Zhuo; Zhao, Xue; Zhou, Tong; Zhang, Siwen; Wang, Guixia (2021). "Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases". Frontiers in Immunology. 12. doi:10.3389/fimmu.2021.648182. ISSN 1664-3224. PMC 8024546. PMID 33841431.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b c van Driel, Boaz Job; Liao, Gongxian; Engel, Pablo; Terhorst, Cox (2016). "Responses to Microbial Challenges by SLAMF Receptors". Frontiers in Immunology. 7. doi:10.3389/fimmu.2016.00004. ISSN 1664-3224. PMC 4718992. PMID 26834746.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b "CD244 CD244 molecule [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov.
- ^ a b c d e f g h i Agresta, Laura; Hoebe, Kasper H. N.; Janssen, Edith M. (2018). "The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment". Frontiers in Immunology. 9. doi:10.3389/fimmu.2018.02809. ISSN 1664-3224. PMC 6279924. PMID 30546369.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b Buller, Casey W.; Mathew, Porunelloor A.; Mathew, Stephen O. (2020). "Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer". Cancers. 12 (7): 1755. doi:10.3390/cancers12071755. ISSN 2072-6694. PMC 7409338. PMID 32630303.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Dragovich, Matthew A.; Mor, Adam (2018). "The SLAM family receptors: Potential therapeutic targets for inflammatory and autoimmune diseases". Autoimmunity Reviews. 17 (7): 674–682. doi:10.1016/j.autrev.2018.01.018. ISSN 1568-9972. PMC 6508580. PMID 29729453.
{{cite journal}}: CS1 maint: PMC format (link)
Further reading
- Vaidya SV, Mathew PA (2006). "Of mice and men: different functions of the murine and human 2B4 (CD244) receptor on NK cells". Immunol. Lett. 105 (2): 180–4. doi:10.1016/j.imlet.2006.02.006. PMID 16621032.
- Siu G, Strauss EC, Lai E, Hood LE (1986). "Analysis of a human V beta gene subfamily". J. Exp. Med. 164 (5): 1600–14. doi:10.1084/jem.164.5.1600. PMC 2188445. PMID 3772297.
- Latchman Y, McKay PF, Reiser H (1998). "Identification of the 2B4 molecule as a counter-receptor for CD48". J. Immunol. 161 (11): 5809–12. doi:10.4049/jimmunol.161.11.5809. PMID 9834056. S2CID 7819238.
- Brown MH, Boles K, van der Merwe PA, et al. (1999). "2B4, the Natural Killer and T Cell Immunoglobulin Superfamily Surface Protein, Is a Ligand for CD48". J. Exp. Med. 188 (11): 2083–90. doi:10.1084/jem.188.11.2083. PMC 2212392. PMID 9841922.
- Tangye SG, Lazetic S, Woollatt E, et al. (1999). "Cutting edge: human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP". J. Immunol. 162 (12): 6981–5. doi:10.4049/jimmunol.162.12.6981. PMID 10358138. S2CID 28826299.
- Nakajima H, Cella M, Langen H, et al. (1999). "Activating interactions in human NK cell recognition: the role of 2B4-CD48". Eur. J. Immunol. 29 (5): 1676–83. doi:10.1002/(SICI)1521-4141(199905)29:05<1676::AID-IMMU1676>3.0.CO;2-Y. PMID 10359122.
- Boles KS, Nakajima H, Colonna M, et al. (1999). "Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4". Tissue Antigens. 54 (1): 27–34. doi:10.1034/j.1399-0039.1999.540103.x. PMID 10458320.
- Kubin MZ, Parshley DL, Din W, et al. (1999). "Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48". Eur. J. Immunol. 29 (11): 3466–77. doi:10.1002/(SICI)1521-4141(199911)29:11<3466::AID-IMMU3466>3.0.CO;2-9. PMID 10556801.
- Parolini S, Bottino C, Falco M, et al. (2000). "X-Linked Lymphoproliferative Disease: 2b4 Molecules Displaying Inhibitory Rather than Activating Function Are Responsible for the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected Cells". J. Exp. Med. 192 (3): 337–46. doi:10.1084/jem.192.3.337. PMC 2193227. PMID 10934222.
- Kumaresan PR, Mathew PA (2000). "Structure of the human natural killer cell receptor 2B4 gene and identification of a novel alternative transcript". Immunogenetics. 51 (11): 987–92. doi:10.1007/s002510000237. PMID 11003394. S2CID 450708.
- Watzl C, Stebbins CC, Long EO (2000). "NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244)". J. Immunol. 165 (7): 3545–8. doi:10.4049/jimmunol.165.7.3545. PMID 11034353.
- Tangye SG, Cherwinski H, Lanier LL, Phillips JH (2001). "2B4-mediated activation of human natural killer cells". Mol. Immunol. 37 (9): 493–501. doi:10.1016/S0161-5890(00)00076-6. PMID 11163399.
- Chuang SS, Pham HT, Kumaresan PR, Mathew PA (2001). "A prominent role for activator protein-1 in the transcription of the human 2B4 (CD244) gene in NK cells". J. Immunol. 166 (10): 6188–95. doi:10.4049/jimmunol.166.10.6188. PMID 11342640.
- Morra M, Simarro-Grande M, Martin M, et al. (2001). "Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients" (PDF). J. Biol. Chem. 276 (39): 36809–16. doi:10.1074/jbc.M101305200. PMID 11477068. S2CID 39889619.
- Morra M, Lu J, Poy F, et al. (2001). "Structural basis for the interaction of the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells". EMBO J. 20 (21): 5840–52. doi:10.1093/emboj/20.21.5840. PMC 125701. PMID 11689425.
- Speiser DE, Colonna M, Ayyoub M, et al. (2002). "The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells". J. Immunol. 167 (11): 6165–70. doi:10.4049/jimmunol.167.11.6165. PMID 11714776.
- Chuang SS, Kumaresan PR, Mathew PA (2002). "2B4 (CD244)-mediated activation of cytotoxicity and IFN-gamma release in human NK cells involves distinct pathways". J. Immunol. 167 (11): 6210–6. doi:10.4049/jimmunol.167.11.6210. PMID 11714782.
- Bottino C, Parolini S, Biassoni R, et al. (2002). "X-linked lymphoproliferative disease: the dark side of 2b4 function". Progress in Basic and Clinical Immunology. Advances in Experimental Medicine and Biology. Vol. 495. pp. 63–7. doi:10.1007/978-1-4615-0685-0_9. ISBN 978-1-4613-5194-8. PMID 11774610.
{{cite book}}:|journal=ignored (help) - Aoukaty A, Tan R (2002). "Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase". J. Biol. Chem. 277 (15): 13331–7. doi:10.1074/jbc.M112029200. PMID 11815622.
- Sivori S, Falco M, Marcenaro E, et al. (2002). "Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation". Proc. Natl. Acad. Sci. U.S.A. 99 (7): 4526–31. Bibcode:2002PNAS...99.4526S. doi:10.1073/pnas.072065999. PMC 123681. PMID 11917118.
- Assarsson E, Kambayshi T, Persson C, et al. (2005). "2B4 co-stimulation: NK cells and their control of adaptive immune responses". Mol. Immunol. 42 (4): 419–23. doi:10.1016/j.molimm.2004.07.021. PMID 15607793.
External links
- CD244+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human CD244 genome location and CD244 gene details page in the UCSC Genome Browser.
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