CD244

Last updated
CD244
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CD244 , 2B4, NAIL, NKR2B4, Nmrk, SLAMF4, CD244 molecule
External IDs OMIM: 605554 MGI: 109294 HomoloGene: 9493 GeneCards: CD244
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001166663
NM_001166664
NM_016382

NM_018729

RefSeq (protein)

NP_001160135
NP_001160136
NP_057466

NP_061199

Location (UCSC) Chr 1: 160.83 – 160.86 Mb Chr 1: 171.39 – 171.44 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

CD244 (Cluster of Differentiation 244) also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene. [5]

Contents

CD244 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. [6] CD244 plays a role in the regulation of the immune system. [7]

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. [6] Only these two receptors from the SLAMF mediate heterophilic interactions. [8] [7]

Gene

The receptor CD244 is encoded by the CD244 gene located on the long arm of human chromosome 1. [8] Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [9] CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells. [8] [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] [6] The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain. [10] [6]

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. [6] 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] [6] 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. [6]

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 the enhancement of their cytolytic activity that they use for killing infected cells. [7] 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 of CD8+ T cells. [7] [9]

Role of CD244 in cancer

NK cells, T cells, dendritic cells, and myeloid-derived suppressor cells in the tumor microenvironment express CD244. [7] The type of the signal is determined by the ratio of expressed CD244 and adaptor protein SAP. However, inhibitory signaling has been shown to predominate in the tumor-associated immune cells. [10]

NK cells and CD8+ T cells use their cytolytic activity to kill tumor cells. Increased CD244 expression in these cells is associated with the inhibitory signal and the exhaustion of the cells. That leads to the impaired antitumor immunity caused by decreased cytotoxicity and proliferation of NK cells and CD8+ T cells. Dendritic cells are important antigen presenting cells. CD244 expression in dendritic cells is also associated with the inhibitory signal due to the low expression of SAP and therefore, they have decreased production of proinflammatory cytokines and reduced ability to activate NK cells and T cells. Myeloid-derived suppressor cells are suppressive cells also found in tumors. Their increased number in the tumor is associated with the progression of the disease. It is known that CD244 signaling in these cells enhances their immunosuppressive capacity resulting in the reduced immune response against tumors. [9]

See also

Related Research Articles

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<span class="mw-page-title-main">LILRB1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">SH2D1A</span> Protein-coding gene in the species Homo sapiens

SH2 domain–containing protein 1A is a protein that in humans is encoded by the SH2D1A gene. It is often called SLAM-associated protein, where "SLAM" refers to signaling lymphocytic activation molecules. It is a SH2 domain–containing molecule that plays a role in SLAM signaling. A putative function is as an adaptor for Fyn and competitor of phosphatases, leading to modulation of SLAM family function. SAP has been implicated in autoimmunity, and a mutation of it is associated with X-linked lymphoproliferative disease. At least 32 disease-causing mutations in this gene have been discovered.

<span class="mw-page-title-main">CD48</span> Protein-coding gene in humans

CD48 antigen also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.

<span class="mw-page-title-main">KIR2DL4</span> Protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the KIR2DL4 gene.

<span class="mw-page-title-main">CD84</span> Protein found in humans

CD84 is a human protein encoded by the CD84 gene.

<span class="mw-page-title-main">CD226</span> Protein-coding gene in the species Homo sapiens

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

<span class="mw-page-title-main">KLRB1</span> Protein-coding gene in humans

Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161, is a human gene.

<span class="mw-page-title-main">SLAMF6</span> Protein-coding gene in humans

SLAM family member 6 is a protein that in humans is encoded by the SLAMF6 gene.

<span class="mw-page-title-main">KLRC2</span> Protein-coding gene in humans

NKG2-C type II integral membrane protein or NKG2C is a protein that in humans is encoded by the KLRC2 gene. It is also known as or cluster of differentiation 159c (CD159c).

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">SLAMF7</span> Protein-coding gene in humans

SLAM family member 7 is a protein that in humans is encoded by the SLAMF7 gene.

<span class="mw-page-title-main">BTLA</span> Protein-coding gene in the species Homo sapiens

B- and T-lymphocyte attenuator or BTLA is a protein that belongs to the CD28 immunoglobulin superfamily (IgSF) which is encoded by the BTLA gene located on the 3rd human chromosome. BTLA was first discovered in 2003 as an inhibitor of Th1 expansion and it became the 3rd member of the CD28 IgSF. However, its discovered ligand herpes virus entry mediator or HVEM belongs to the tumor necrosis factor receptor superfamily (TNFRSF). This finding was surprising because until the discovery of HVEM it was believed that receptors and ligands always belong to the same family.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

<span class="mw-page-title-main">KLRG1</span> Protein-coding gene in humans

Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.

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<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Paired receptors</span>

Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000122223 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000004709 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: CD244 CD244 molecule, natural killer cell receptor 2B4".
  6. 1 2 3 4 5 6 7 Pahima H, Puzzovio PG, Levi-Schaffer F (July 2019). "2B4 and CD48: A powerful couple of the immune system". Clinical Immunology. 204: 64–68. doi:10.1016/j.clim.2018.10.014. PMID   30366105. S2CID   53091716.
  7. 1 2 3 4 5 Sun L, Gang X, Li Z, Zhao X, Zhou T, Zhang S, Wang G (2021). "Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases". Frontiers in Immunology. 12: 648182. doi: 10.3389/fimmu.2021.648182 . PMC   8024546 . PMID   33841431.
  8. 1 2 3 van Driel BJ, Liao G, Engel P, Terhorst C (2016). "Responses to Microbial Challenges by SLAMF Receptors". Frontiers in Immunology. 7: 4. doi: 10.3389/fimmu.2016.00004 . PMC   4718992 . PMID   26834746.
  9. 1 2 3 4 5 6 7 8 9 10 Agresta L, Hoebe KH, Janssen EM (2018). "The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment". Frontiers in Immunology. 9: 2809. doi: 10.3389/fimmu.2018.02809 . PMC   6279924 . PMID   30546369.
  10. 1 2 3 Buller CW, Mathew PA, Mathew SO (July 2020). "Roles of NK Cell Receptors 2B4 (CD244), CS1 (CD319), and LLT1 (CLEC2D) in Cancer". Cancers. 12 (7): 1755. doi: 10.3390/cancers12071755 . PMC   7409338 . PMID   32630303.
  11. Dragovich MA, Mor A (July 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. PMC   6508580 . PMID   29729453.

Further reading