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Showing Protein Triggering receptor expressed on myeloid cells 2 (HMDBP13856)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 1 metabolite
Identification
HMDB Protein ID HMDBP13856
Secondary Accession Numbers None
Name Triggering receptor expressed on myeloid cells 2
Synonyms
  1. TREM-2
  2. Triggering receptor expressed on monocytes 2
Gene Name TREM2
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia (PubMed:27477018, PubMed:29518356). Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1 (By similarity). Acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU and enhances their uptake in microglia (PubMed:27477018). Binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin (PubMed:29794134). Regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade (By similarity). Required for microglial phagocytosis of apoptotic neurons (PubMed:24990881). Also required for microglial activation and phagocytosis of myelin debris after neuronal injury and of neuronal synapses during synapse elimination in the developing brain (By similarity). Regulates microglial chemotaxis and process outgrowth, and also the microglial response to oxidative stress and lipopolysaccharide (By similarity). It suppresses PI3K and NF-kappa-B signaling in response to lipopolysaccharide; thus promoting phagocytosis, suppressing pro-inflammatory cytokine and nitric oxide production, inhibiting apoptosis and increasing expression of IL10 and TGFB (By similarity). During oxidative stress, it promotes anti-apoptotic NF-kappa-B signaling and ERK signaling (By similarity). Plays a role in microglial MTOR activation and metabolism (By similarity). Regulates age-related changes in microglial numbers (PubMed:29752066). Triggers activation of the immune responses in macrophages and dendritic cells (PubMed:10799849). Mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (By similarity). In dendritic cells, it mediates up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Involved in the positive regulation of osteoclast differentiation (PubMed:12925681).
Pathways
  • Osteoclast differentiation
Reactions Not Available
GO Classification
Biological Process
cellular response to lipoteichoic acid
dendritic cell differentiation
positive regulation of interleukin-10 production
defense response to bacterium
negative regulation of apoptotic process
phagocytosis, engulfment
negative regulation of interleukin-1 beta production
positive regulation of protein secretion
negative regulation of tumor necrosis factor production
regulation of interleukin-6 production
regulation of peptidyl-tyrosine phosphorylation
positive regulation of protein phosphorylation
regulation of innate immune response
positive regulation of protein localization to plasma membrane
amyloid-beta clearance
astrocyte activation
positive regulation of ERK1 and ERK2 cascade
cellular response to peptidoglycan
complement-mediated synapse pruning
detection of lipoteichoic acid
detection of peptidoglycan
import into cell
microglial cell activation involved in immune response
positive regulation of peptidyl-tyrosine phosphorylation
microglial cell proliferation
negative regulation of autophagic cell death
neuroinflammatory response
osteoclast differentiation
positive regulation of amyloid-beta clearance
positive regulation of antigen processing and presentation of peptide antigen via MHC class II
positive regulation of phagocytosis, engulfment
positive regulation of ATP biosynthetic process
positive regulation of C-C chemokine receptor CCR7 signaling pathway
positive regulation of CAMKK-AMPK signaling cascade
positive regulation of CD40 signaling pathway
positive regulation of engulfment of apoptotic cell
positive regulation of inward rectifier potassium channel activity
detection of lipopolysaccharide
positive regulation of macrophage fusion
innate immune response
positive regulation of microglial cell activation
positive regulation of microglial cell migration
positive regulation of mitochondrion organization
positive regulation of TOR signaling
humoral immune response
regulation of intracellular signal transduction
regulation of macrophage inflammatory protein 1 alpha production
regulation of plasma membrane bounded cell projection organization
regulation of resting membrane potential
positive regulation of osteoclast differentiation
response to ischemia
cellular response to amyloid-beta
microglial cell activation
regulation of gene expression
positive regulation of gene expression
positive regulation of calcium-mediated signaling
regulation of immune response
apoptotic cell clearance
regulation of TOR signaling cascade
positive regulation of NIK/NF-kappaB signaling
negative regulation of autophagy
positive regulation of chemotaxis
positive regulation of proteasomal protein catabolic process
Cellular Component
intrinsic component of plasma membrane
plasma membrane
plasma membrane raft
extracellular region
integral to membrane
integral to plasma membrane
Molecular Function
lipopolysaccharide binding
peptidoglycan binding
protein-containing complex binding
beta-amyloid binding
apolipoprotein binding
low-density lipoprotein particle binding
lipid binding
phospholipid binding
scaffold protein binding
apolipoprotein A-I binding
high-density lipoprotein particle binding
lipoprotein particle binding
very-low-density lipoprotein particle binding
lipoteichoic acid binding
transmembrane signaling receptor activity
signaling receptor activity
protein tyrosine kinase binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 230
Molecular Weight 25446.755
Theoretical pI 6.3
Pfam Domain Function
Signals
  • 1-18;
Transmembrane Regions
  • 175-195;
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q9NZC2
UniProtKB/Swiss-Prot Entry Name TREM2_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  2. Bouchon A, Dietrich J, Colonna M: Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000 May 15;164(10):4991-5. doi: 10.4049/jimmunol.164.10.4991. [PubMed:10799849 ]
  3. Bouchon A, Hernandez-Munain C, Cella M, Colonna M: A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med. 2001 Oct 15;194(8):1111-22. doi: 10.1084/jem.194.8.1111. [PubMed:11602640 ]
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  5. Klunemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J: The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005 May 10;64(9):1502-7. doi: 10.1212/01.WNL.0000160304.00003.CA. [PubMed:15883308 ]
  6. Helming L, Tomasello E, Kyriakides TR, Martinez FO, Takai T, Gordon S, Vivier E: Essential role of DAP12 signaling in macrophage programming into a fusion-competent state. Sci Signal. 2008 Oct 28;1(43):ra11. doi: 10.1126/scisignal.1159665. [PubMed:18957693 ]
  7. Zhong L, Chen XF, Zhang ZL, Wang Z, Shi XZ, Xu K, Zhang YW, Xu H, Bu G: DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response. J Biol Chem. 2015 Jun 19;290(25):15866-15877. doi: 10.1074/jbc.M115.645986. Epub 2015 May 8. [PubMed:25957402 ]
  8. Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J: Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J Biol Chem. 2013 Nov 15;288(46):33027-36. doi: 10.1074/jbc.M113.517540. Epub 2013 Sep 27. [PubMed:24078628 ]
  9. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleo A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sanchez-Valle R, Antonell A, Ramirez A, Heneka MT, Sleegers K, van der Zee J, Martin JJ, Engelborghs S, Demirtas-Tatlidede A, Zetterberg H, Van Broeckhoven C, Gurvit H, Wyss-Coray T, Hardy J, Colonna M, Haass C: TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. doi: 10.1126/scitranslmed.3009093. [PubMed:24990881 ]
  10. Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EM, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS: Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. doi: 10.1186/s40478-016-0367-7. [PubMed:27589997 ]
  11. Jiang T, Tan L, Chen Q, Tan MS, Zhou JS, Zhu XC, Lu H, Wang HF, Zhang YD, Yu JT: A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. doi: 10.1016/j.neurobiolaging.2016.02.023. Epub 2016 Mar 3. [PubMed:27067662 ]
  12. Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M: TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016 Jul 20;91(2):328-40. doi: 10.1016/j.neuron.2016.06.015. [PubMed:27477018 ]
  13. Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou Y, Cairns NJ, Kambal A, Loginicheva E, Gilfillan S, Cella M, Virgin HW, Unanue ER, Wang Y, Artyomov MN, Holtzman DM, Colonna M: TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. doi: 10.1016/j.cell.2017.07.023. [PubMed:28802038 ]
  14. Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C: An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med. 2017 Oct;9(10):1356-1365. doi: 10.15252/emmm.201707672. [PubMed:28855300 ]
  15. Thornton P, Sevalle J, Deery MJ, Fraser G, Zhou Y, Stahl S, Franssen EH, Dodd RB, Qamar S, Gomez Perez-Nievas B, Nicol LS, Eketjall S, Revell J, Jones C, Billinton A, St George-Hyslop PH, Chessell I, Crowther DC: TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant. EMBO Mol Med. 2017 Oct;9(10):1366-1378. doi: 10.15252/emmm.201707673. [PubMed:28855301 ]
  16. Sirkis DW, Aparicio RE, Schekman R: Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER-Golgi intermediate compartment. Mol Biol Cell. 2017 Oct 1;28(20):2723-2733. doi: 10.1091/mbc.E17-06-0423. Epub 2017 Aug 2. [PubMed:28768830 ]
  17. Claes C, Van Den Daele J, Boon R, Schouteden S, Colombo A, Monasor LS, Fiers M, Ordovas L, Nami F, Bohrmann B, Tahirovic S, De Strooper B, Verfaillie CM: Human stem cell-derived monocytes and microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2. Alzheimers Dement. 2019 Mar;15(3):453-464. doi: 10.1016/j.jalz.2018.09.006. Epub 2018 Nov 12. [PubMed:30442540 ]
  18. Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, Erreni M, Markicevic M, Starvaggi-Cucuzza C, Otero K, Piccio L, Cignarella F, Perrucci F, Tamborini M, Genua M, Rajendran L, Menna E, Vetrano S, Fahnestock M, Paolicelli RC, Matteoli M: The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity. Immunity. 2018 May 15;48(5):979-991.e8. doi: 10.1016/j.immuni.2018.04.016. Epub 2018 May 8. [PubMed:29752066 ]
  19. Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, Sun Y, Zhu B, Pina-Crespo JC, Zhang M, Zhang N, Chen X, Bu G, An Z, Huang TY, Xu H: TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. Neuron. 2018 Mar 7;97(5):1023-1031.e7. doi: 10.1016/j.neuron.2018.01.031. [PubMed:29518356 ]
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  22. Soragna D, Papi L, Ratti MT, Sestini R, Tupler R, Montalbetti L: An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):825-6. doi: 10.1136/jnnp.74.6.825-a. [PubMed:12754369 ]
  23. Bock V, Botturi A, Gaviani P, Lamperti E, Maccagnano C, Piccio L, Silvani A, Salmaggi A: Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature. J Neurol Sci. 2013 Mar 15;326(1-2):115-9. doi: 10.1016/j.jns.2013.01.021. Epub 2013 Feb 9. [PubMed:23399524 ]
  24. Park JS, Ji IJ, An HJ, Kang MJ, Kang SW, Kim DH, Yoon SY: Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus. Traffic. 2015 May;16(5):510-8. doi: 10.1111/tra.12264. Epub 2015 Feb 24. [PubMed:25615530 ]
  25. Ghezzi L, Carandini T, Arighi A, Fenoglio C, Arcaro M, De Riz M, Pietroboni AM, Fumagalli GG, Basilico P, Calvi A, Scarioni M, Colombi A, Serpente M, Marotta G, Benti R, Scarpini E, Galimberti D: Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation. Neurology. 2017 Dec 12;89(24):2503-2505. doi: 10.1212/WNL.0000000000004747. Epub 2017 Nov 15. [PubMed:29142083 ]