Signaling lymphocytic activation molecule

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Signaling lymphocytic activation molecule
Identifiers
SymbolSLAM
Pfam PF06214
InterPro IPR010407
Membranome 164
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Signaling lymphocytic activation molecule (SLAM) is a family of genes. Homophilic binding between SLAMs is involved in cell-to-cell adhesion during antigen presentation. [1] [2]

Contents

Signaling lymphocytic activation molecules are a CD2-related surface receptor expressed by activated phagocytes, T helper cells, and platelets. [3] SLAMs have a variety of functions, including enhancing T cellular proliferation by stimulating IL-4 and IFN-gamma production. [4] SLAM family (SLAMF) receptors can interact directly with microbes, which can cause phagocytic cells to migrate to the area. [5] SLAMF activation can trigger SLAM-associated protein (SAP) activation and a defective SAP can cause X-linked lymphoproliferative syndrome (XLP). [4]

Family members

Members of the family include:

Location and function

SLAMFs are CD2-related surface receptors expressed by activated B and T cells, natural killer (NK) cells, dendritic cells, macrophages, eosinophils, neutrophils, and platelets, although different SLAMF receptors have varying expression patterns. [4] SLAMF receptors are cell surface transmembrane molecules that can interact directly with microbes, which can cause phagocytic cells to migrate to the area. [11] SLAMF1 and SLAMF6 are known to directly interact with outer membrane porins on gram negative bacteria. [3] SLAMF1 is a known receptor for the measles virus and also serves as an opsonin for phagocytic cells, enhancing phagocytosis by localizing to phagosomes and inducing a signaling cascade resulting in enhanced fusion of phagosomes and lysosomes. [3] [5] SLAMF2 is known bind gram negative bacteria and is internalized after binding, promoting phagocytosis. [3] SLAMFs are also involved in immune cell communication; SLAMFs are co-stimulatory molecules for both T-cells and NK cells. SLAMs enhance T helper cell proliferation by increasing IFN-gamma and IL-4 production. [11]

Structure

This diagram shows the signaling pathway for a SLAMF1 receptor in a CD4 T-helper cell. It depicts SAP (Slam-Associated Protein) outcompeting EAT-2 (Ewing's sarcoma-associated transcript 2) using a 3-pronged binding pattern to ITSMs on the SLAMF. The ITSMs do not necessarily need to be phosphorylated for SAP to bind, but they do need to be phosphorylated for EAT-2 to bind. SAP binding leads to Fyn recruitment and eventually IL-4 and IFN-gamma release. SLAM signaling.png
This diagram shows the signaling pathway for a SLAMF1 receptor in a CD4 T-helper cell. It depicts SAP (Slam-Associated Protein) outcompeting EAT-2 (Ewing’s sarcoma-associated transcript 2) using a 3-pronged binding pattern to ITSMs on the SLAMF. The ITSMs do not necessarily need to be phosphorylated for SAP to bind, but they do need to be phosphorylated for EAT-2 to bind. SAP binding leads to Fyn recruitment and eventually IL-4 and IFN-gamma release.

All members of the SLAMF family are classified as type I glycoproteins and share an amino-terminal IgV variable domain and a membrane-adjacent IgC2 constant domain, along with immunoreceptor tyrosine-based switch motifs (ITSMs). [11] [4] The IgV and IgC2 domains are located on the extracellular portion of the receptor, while the ITSMs are used for signaling within the cell. SLAMFs can undergo alternative splicing, which can generate different isoforms of the SLAMF molecules that have different numbers of ITSMs and tyrosines, potentially with different functions. [4] Proteins with SH2 domains are able to bind these ITSMs to initiate signaling cascades within the cell. SLAMF2 and SLAMF4 interact with one another, but all other SLAMF receptors are self-ligands, meaning that they interact with the corresponding receptor on other cells in a homophilic way. [3]

Uses in immunotherapy

SLAMFs are potential targets for immunotherapy. For example, elotuzumab is an anti-SLAMF7 humanized monoclonal antibody used to treat multiple myeloma. SLAMF7 is a self-ligand over-expressed in plasma cells of multiple myeloma patients. Elotuzumab stimulates NK cells to release granzyme through blocking SLAMF7, through triggering antibody-dependent cellular cytotoxicity (ADCC), and through NK cell activation via Ewing’s sarcoma-associated transcript 2 (EAT-2). [12] EAT-2 is known to bind to phosphorylated tyrosines on ITSMs and alter cytokine production. [5] Elotuzumab also blocks multiple myeloma cells from interacting with one another via the SLAMF7 ligand. [13]

SLAM-associated protein (SAP)

The X-linked SLAM-associated protein (SAP), encoded by the SH2D1A gene, consists primarily of an SH2 domain which can interact with ITSMs present on most SLAMF receptors. [3] [4] Unlike most SH2 binding proteins, SAP does not require tyrosines on the ITSMs to be phosphorylated prior to binding. [4] SAP is expressed in lymphocytes (specifically NK cells and T cells, but not usually B cells), eosinophils, and platelets. [4] [3] A defective SLAM associated protein (SAP) causes X-linked lymphoproliferative syndrome (XLP), a frequently lethal mononucleosis characterized by inability to respond to infection with Epstein-Barr virus (EBV), leading to a failure to clear B-cells infected with the virus, which can be fatal. [3]

Related Research Articles

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<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

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<span class="mw-page-title-main">ZAP70</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Lymphocyte cytosolic protein 2</span> Protein-coding gene in the species Homo sapiens

Lymphocyte cytosolic protein 2, also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell receptors (TCRs). As an adaptor protein, SLP-76 does not have catalytic functions, primarily binding other signaling proteins to form larger signaling complexes. It is a key component of the signaling pathways of receptors with immunoreceptor tyrosine-based activation motifs (ITAMs) such as T-cell receptors, its precursors, and receptors for the Fc regions of certain antibodies. SLP-76 is expressed in T-cells and related lymphocytes like natural killer cells.

An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acid serine, I is the amino acid isoleucine, and V is the amino acid valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

<span class="mw-page-title-main">Linker for activation of T cells</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">Signal-regulatory protein alpha</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">CD244</span> Protein found in humans

CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

<span class="mw-page-title-main">SLAMF1</span> Protein-coding gene in humans

Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.

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

FYN binding protein (FYB-120/130), also known as FYB, ADAP, and SLAP-130 is a protein that is encoded by the FYB gene in humans. The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells. FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.

<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">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">CD200</span> Protein-coding gene in the species Homo sapiens

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

<span class="mw-page-title-main">SH2D1B</span> Protein-coding gene in the species Homo sapiens

SH2 domain-containing protein 1B is a protein that in humans is encoded by the SH2D1B gene.

X-linked lymphoproliferative disease is a lymphoproliferative disorder, usually caused by SH2DIA gene mutations in males. XLP-positive individuals experience immune system deficiencies that render them unable to effectively respond to the Epstein-Barr virus (EBV), a common virus in humans that typically induces mild symptoms or infectious mononucleosis (IM) in patients. There are two currently known variations of the disorder, known as XLP1 and XLP2. XLP1 is estimated to occur in approximately one in every million males, while XLP2 is rarer, estimated to occur in one of every five million males. Due to therapies such as chemotherapy and stem cell transplants, the survival rate of XLP1 has increased dramatically since its discovery in the 1970s.

Non-catalytic tyrosine-phosphorylated receptors (NTRs), also called immunoreceptors or Src-family kinase-dependent receptors, are a group of cell surface receptors expressed by leukocytes that are important for cell migration and the recognition of abnormal cells or structures and the initiation of an immune response. These transmembrane receptors are not grouped into the NTR family based on sequence homology, but because they share a conserved signalling pathway utilizing the same signalling motifs. A signaling cascade is initiated when the receptors bind their respective ligand resulting in cell activation. For that tyrosine residues in the cytoplasmic tail of the receptors have to be phosphorylated, hence the receptors are referred to as tyrosine-phosphorylated receptors. They are called non-catalytic receptors, as the receptors have no intrinsic tyrosine kinase activity and cannot phosphorylate their own tyrosine residues. Phosphorylation is mediated by additionally recruited kinases. A prominent member of this receptor family is the T-cell receptor.

References

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