TREM2

Official Full Name

triggering receptor expressed on myeloid cells 2

Organism

Homo sapiens

GeneID

54209

Background

This gene encodes a membrane protein that forms a receptor signaling complex with the TYRO protein tyrosine kinase binding protein. The encoded protein functions in immune response and may be involved in chronic inflammation by triggering the production of constitutive inflammatory cytokines. Defects in this gene are a cause of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2012]

Synonyms

AD17; PLOSL2; TREM-2; Trem2a; Trem2b; Trem2c;

Protein Sequence

MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDCGHDPGYQLQTLPGLRDT

Open

Disease

Alzheimer disease

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Tag	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

Triggering receptor expression on myeloid cells-2 (TREM2) is an extracellular innate immune receptor expressed on myeloid lineage cells such as dendritic cells (DC) and resident tissue macrophages (including microglia and osteoclasts). The importance of TREM2 is emphasized by genetic studies linking TREM2 variants to various neurodegenerative diseases, including Alzheimer's disease (AD). TREM2 has been implicated in a wide array of functions including cell maturation, survival, proliferation, phagocytosis, activation, and the regulation of inflammation. Studies from cultured microglia or bone marrow-derived macrophages have shown that TREM2 is very important for the phagocytosis of apoptotic cells and bacteria. TREM2-DAP12 signaling cooperates with activation of the CSF1R to promote the survival and proliferation of macrophages. TREM2 activity is also important for inhibiting inflammation following activation of Toll-like receptors (TLRs).

TREM2 Regulation and Signaling

TREM2 has an extracellular Ig-like ligand-binding domain, and its transmembrane region bears a positively charged lysine residue, which interacts with its signaling partner TYROBP. However, the short cytoplasmic tail of TREM2 has no function. It is known that TREM2 ligation induces phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in TYROBP by Src family kinases. Studies in human and mouse cells have demonstrated that the tyrosine-phosphorylated ITAM domain recruits Syk and/or ZAP-70 kinases to transduce downstream signals through the extracellular signal-regulated kinases (ERK), intracellular Ca²⁺ signaling, phosphoinositide 3-kinase (PI3K), and actin reorganization pathways, resulting in cellular activities including promotion of phagocytosis and NFAT (nuclear factor of activated T cells)-dependent transcriptional activation. One report also implicated the signaling adaptor DAP10, a relative of TYROBP, in TREM2-mediated signal transduction, and DAP10 was necessary for the recruitment of PI3K to the membrane signaling complex. It also reported that the SH2 domain-containing inositol phosphatase (SHIP) – the product of INPP5D, another AD-associated gene –limited TREM2–TYROBP signaling by binding to TYROBP and preventing PI3K recruitment.

Figure 1. Regulation of TREM2 Signaling. (Yeh F L, et al., 2017)

TREM2 and Alzheimer’s Disease

Whole-genome sequencing studies resulted in the discovery of rare variants in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) that increase the risk of developing AD through ∼2- to 3-fold. Several variants in TREM2 appear to significantly increase the risk of developing AD. The most common variant within TREM2 that is now firmly established as increasing the risk for AD is rs75932628, an SNP that confers an Arg-to-His change at amino acid 47. In humans, the gene encoding TREM2 is located in a group of related TREM genes (TREM1, TREM2, TREM4, and TREM5) at chromosome 6p21.1. Two other TREM-like genes, TREML1 and TREML2, are also located within the TREM gene cluster. Variants in other genes in the TREM gene cluster, such as rs6910730G in TREM1, may also be associated with an increased risk of AD pathology.

AD-associated variants do seem to affect the affinity of TREM2 for its ligands. In fact, binding assays showed that R47H, R62H and D87N variants exhibit impaired interactions with lipoprotein ligands including LDL, ApoE, and clusterin in vitro. In contrast, Kober et al. reported that the T96K variant increased TREM2 affinity to cell-surface ligands, while confirming reduced binding of cell-surface ligands by R47H. AD-associated variants disturb TREM2 signaling in a pattern similar to that observed for affinity: R47H and R62H negatively affect TREM2 activity in vitro, while T96K activity was enhanced than the common variant of TREM2. However, this correlation between affinity and signaling strength does not apply to the D87N variant, which results in reduced ligand binding but an increase in TREM2 signaling. Finally, R47H and R62H variants have been shown to slightly alter phagocytic functions of TREM2 in vitro. In addition, R47H missense mutation impairs TREM2 maturation and alters shedding by α-secretase.

References:

Kober D L, Brett T J. TREM2-ligand interactions in health and disease. Journal of molecular biology, 2017, 429(11): 1607-1629.
Hickman S E, El Khoury J. TREM2 and the neuroimmunology of Alzheimer's disease. Biochemical pharmacology, 2014, 88(4): 495-498.
Ulrich J D, Holtzman D M. TREM2 function in Alzheimer's disease and neurodegeneration. ACS chemical neuroscience, 2016, 7(4): 420-427.
Yeh F L, et al. TREM2, microglia, and neurodegenerative diseases. Trends in molecular medicine, 2017, 23(6): 512-533.
Ulland T K, Colonna M. TREM2—a key player in microglial biology and Alzheimer disease. Nature Reviews Neurology, 2018, 14(11): 667-675.
Gratuze M, et al. New insights into the role of TREM2 in Alzheimer's disease. Molecular neurodegeneration, 2018, 13(1): 1-16.
Ulrich J D, et al. Elucidating the role of TREM2 in Alzheimer's disease. Neuron, 2017, 94(2): 237-248.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry