Recombinant Human Triggering receptor expressed on myeloid cells 2 (TREM2), partial (Active)

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, receptor of SEMA6D with PLEXNA1 as coreceptor and 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)

Subcellular Location

Secreted

Disease Association

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2 (PLOSL2) : An autosomal recessive disease characterized by presenile frontal dementia with leukoencephalopathy and basal ganglia calcification. In most cases the disorder first manifests in early adulthood as pain and swelling in ankles and feet, followed by bone fractures. Neurologic symptoms manifest in the fourth decade of life as a frontal lobe syndrome with loss of judgment, euphoria, and disinhibition. Progressive decline in other cognitive domains begins to develop at about the same time. The disorder culminates in a profound dementia and death by age 50 years. [The disease is caused by variants affecting the gene represented in this entry] | Alzheimer disease 17 (AD17) : A late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. [Disease susceptibility is associated with variants affecting the gene represented in this entry]

Tissue Specificity

Expressed in the brain, specifically in microglia and in the fusiform gyrus (at protein level) (PubMed:27477018, PubMed:28802038, PubMed:28855300, PubMed:29752066). Expressed on macrophages and dendritic cells but not on granulocytes or monocytes (PubMed:10799849, PubMed:28855301). In the CNS strongest expression seen in the basal ganglia, corpus callosum, medulla oblongata and spinal cord (PubMed:12080485)

Subunit

Monomer (PubMed:27995897). After ectodomain shedding, the extracellular domain oligomerizes, which is enhanced and stabilized by binding of phosphatidylserine (PubMed:29794134). Interacts with TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with TYROBP is required for stabilization of the TREM2 C-terminal fragment (TREM2-CTF) which is produced by proteolytic processing (PubMed:25957402). Interacts with PLXNA1 (via TIG domains); the interaction mediates SEMA6D binding and signaling through TYROBP (By similarity)

• Bouchon A. et al. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. — J. Immunol. (2000)
• Begum N.A. et al. Identification of a novel variant of triggering receptor, TREM-2V, by mRNA differential display. (JUN-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Bouchon A. et al. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. — J. Exp. Med. (2001)
• Paloneva J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. — Am. J. Hum. Genet. (2002)
• Paloneva J. et al. PubMed: CI-4U06QQ06429DB — Am. J. Hum. Genet. (2003)
• Paloneva J. et al. DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. — J. Exp. Med. (2003)
• Kluenemann H.H. et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. — Neurology (2005)