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Signaling lymphocytic activation molecule

January 01, 1970

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]

Signaling lymphocytic activation molecule
Identifiers
SymbolSLAM
PfamPF06214
InterProIPR010407
Membranome164
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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 edit

Members of the family include:

Location and function edit

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 edit

 
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 edit

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) edit

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]

References edit

  1. ^ "SLAM FAMILY, MEMBER 1". OMIM. Retrieved 19 March 2014.
  2. ^ Rosenbach T, Csatò M, Czarnetzki BM (January 1988). "Studies on the role of leukotrienes in murine allergic and irritant contact dermatitis". The British Journal of Dermatology. 118 (1): 1–6. doi:10.1111/j.1365-2133.1988.tb01743.x. PMID 2829957. S2CID 1164113.
  3. ^ a b c d e f g h Detre C, Keszei M, Romero X, Tsokos GC, Terhorst C (2010-06-01). "SLAM family receptors and the SLAM-associated protein (SAP) modulate T cell functions". Seminars in Immunopathology. 32 (2): 157–171. doi:10.1007/s00281-009-0193-0. ISSN 1863-2300. PMC 2868096. PMID 20146065.
  4. ^ a b c d e f g h i j Cannons JL, Tangye SG, Schwartzberg PL (2011-04-23). "SLAM Family Receptors and SAP Adaptors in Immunity". Annual Review of Immunology. 29 (1): 665–705. doi:10.1146/annurev-immunol-030409-101302. ISSN 0732-0582. PMID 21219180.
  5. ^ a b c van Driel BJ, Liao G, Engel P, Terhorst C (2016-01-20). "Responses to Microbial Challenges by SLAMF Receptors". Frontiers in Immunology. 7: 4. doi:10.3389/fimmu.2016.00004. PMC 4718992. PMID 26834746.
  6. ^ Sintes J, Engel P (February 2011). "SLAM (CD150) is a multitasking immunoreceptor: from cosignalling to bacterial recognition". Immunology and Cell Biology. 89 (2): 161–3. doi:10.1038/icb.2010.145. PMID 21102539. S2CID 31409234.
  7. ^ Chatterjee M, Kis-Toth K, Thai TH, Terhorst C, Tsokos GC (May 2011). "SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells". Autoimmunity. 44 (3): 211–8. doi:10.3109/08916934.2010.530627. PMC 4465387. PMID 21231893.
  8. ^ Kim JR, Horton NC, Mathew SO, Mathew PA (August 2013). "CS1 (SLAMF7) inhibits production of proinflammatory cytokines by activated monocytes". Inflammation Research. 62 (8): 765–72. doi:10.1007/s00011-013-0632-1. PMID 23695528. S2CID 11918450.
  9. ^ Wang G, Abadía-Molina AC, Berger SB, Romero X, O'Keeffe MS, Rojas-Barros DI, Aleman M, Liao G, Maganto-García E, Fresno M, Wang N, Detre C, Terhorst C (June 2012). "Cutting edge: Slamf8 is a negative regulator of Nox2 activity in macrophages". Journal of Immunology. 188 (12): 5829–32. doi:10.4049/jimmunol.1102620. PMC 3370125. PMID 22593622.
  10. ^ Pott S, Kamrani NK, Bourque G, Pettersson S, Liu ET (2012). Jothi R (ed.). "PPARG binding landscapes in macrophages suggest a genome-wide contribution of PU.1 to divergent PPARG binding in human and mouse". PLOS ONE. 7 (10): e48102. Bibcode:2012PLoSO...748102P. doi:10.1371/journal.pone.0048102. PMC 3485280. PMID 23118933.
  11. ^ a b c van Driel BJ, Liao G, Engel P, Terhorst C (2016-01-20). "Responses to Microbial Challenges by SLAMF Receptors". Frontiers in Immunology. 7: 4. doi:10.3389/fimmu.2016.00004. ISSN 1664-3224. PMC 4718992. PMID 26834746.
  12. ^ Ritchie D, Colonna M (May 2018). "Mechanisms of Action and Clinical Development of Elotuzumab: Development of Elotuzumab in Myeloma". Clinical and Translational Science. 11 (3): 261–266. doi:10.1111/cts.12532. PMC 5944582. PMID 29272564.
  13. ^ Sell S (June 2017). "Cancer immunotherapy: Breakthrough or "deja vu, all over again"?". Tumor Biology. 39 (6): 101042831770776. doi:10.1177/1010428317707764. ISSN 1010-4283. PMID 28639883.

January 01, 1970
signaling, lymphocytic, activation, molecule, slam, family, genes, homophilic, binding, between, slams, involved, cell, cell, adhesion, during, antigen, presentation, identifierssymbolslampfampf06214interproipr010407membranome164available, protein, structures,. 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 Signaling lymphocytic activation moleculeIdentifiersSymbolSLAMPfamPF06214InterProIPR010407Membranome164Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summary 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 Contents 1 Family members 2 Location and function 3 Structure 4 Uses in immunotherapy 5 SLAM associated protein SAP 6 ReferencesFamily members editMembers of the family include SLAMF1 CD150 SLAMF2 CD48 FimH 6 4 SLAMF3 CD229 LY9 SLAMF4 CD244 2B4 SLAMF5 CD84 SLAMF6 CD352 7 SLAMF7 CD319 CRACC 8 4 SLAMF8 CD353 9 SLAMF9 10 Location and function editSLAMFs 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 edit nbsp 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 editSLAMFs 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 editThe 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 References edit SLAM FAMILY MEMBER 1 OMIM Retrieved 19 March 2014 Rosenbach T Csato M Czarnetzki BM January 1988 Studies on the role of leukotrienes in murine allergic and irritant contact dermatitis The British Journal of Dermatology 118 1 1 6 doi 10 1111 j 1365 2133 1988 tb01743 x PMID 2829957 S2CID 1164113 a b c d e f g h Detre C Keszei M Romero X Tsokos GC Terhorst C 2010 06 01 SLAM family receptors and the SLAM associated protein SAP modulate T cell functions Seminars in Immunopathology 32 2 157 171 doi 10 1007 s00281 009 0193 0 ISSN 1863 2300 PMC 2868096 PMID 20146065 a b c d e f g h i j Cannons JL Tangye SG Schwartzberg PL 2011 04 23 SLAM Family Receptors and SAP Adaptors in Immunity Annual Review of Immunology 29 1 665 705 doi 10 1146 annurev immunol 030409 101302 ISSN 0732 0582 PMID 21219180 a b c van Driel BJ Liao G Engel P Terhorst C 2016 01 20 Responses to Microbial Challenges by SLAMF Receptors Frontiers in Immunology 7 4 doi 10 3389 fimmu 2016 00004 PMC 4718992 PMID 26834746 Sintes J Engel P February 2011 SLAM CD150 is a multitasking immunoreceptor from cosignalling to bacterial recognition Immunology and Cell Biology 89 2 161 3 doi 10 1038 icb 2010 145 PMID 21102539 S2CID 31409234 Chatterjee M Kis Toth K Thai TH Terhorst C Tsokos GC May 2011 SLAMF6 driven co stimulation of human peripheral T cells is defective in SLE T cells Autoimmunity 44 3 211 8 doi 10 3109 08916934 2010 530627 PMC 4465387 PMID 21231893 Kim JR Horton NC Mathew SO Mathew PA August 2013 CS1 SLAMF7 inhibits production of proinflammatory cytokines by activated monocytes Inflammation Research 62 8 765 72 doi 10 1007 s00011 013 0632 1 PMID 23695528 S2CID 11918450 Wang G Abadia Molina AC Berger SB Romero X O Keeffe MS Rojas Barros DI Aleman M Liao G Maganto Garcia E Fresno M Wang N Detre C Terhorst C June 2012 Cutting edge Slamf8 is a negative regulator of Nox2 activity in macrophages Journal of Immunology 188 12 5829 32 doi 10 4049 jimmunol 1102620 PMC 3370125 PMID 22593622 Pott S Kamrani NK Bourque G Pettersson S Liu ET 2012 Jothi R ed PPARG binding landscapes in macrophages suggest a genome wide contribution of PU 1 to divergent PPARG binding in human and mouse PLOS ONE 7 10 e48102 Bibcode 2012PLoSO 748102P doi 10 1371 journal pone 0048102 PMC 3485280 PMID 23118933 a b c van Driel BJ Liao G Engel P Terhorst C 2016 01 20 Responses to Microbial Challenges by SLAMF Receptors Frontiers in Immunology 7 4 doi 10 3389 fimmu 2016 00004 ISSN 1664 3224 PMC 4718992 PMID 26834746 Ritchie D Colonna M May 2018 Mechanisms of Action and Clinical Development of Elotuzumab Development of Elotuzumab in Myeloma Clinical and Translational Science 11 3 261 266 doi 10 1111 cts 12532 PMC 5944582 PMID 29272564 Sell S June 2017 Cancer immunotherapy Breakthrough or deja vu all over again Tumor Biology 39 6 101042831770776 doi 10 1177 1010428317707764 ISSN 1010 4283 PMID 28639883 Retrieved from https en wikipedia org w index php title Signaling lymphocytic activation molecule amp oldid 1195579519, wikipedia, wiki, book, books, library,

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