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Review
. 2016 Feb 26;291(9):4334-41.
doi: 10.1074/jbc.R115.704981. Epub 2015 Dec 22.

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

Jochen Walter  1
Affiliations
Review

The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases

Jochen Walter. J Biol Chem. .

Abstract

The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12 kDa (DAP12). Homozygous mutations in TREM2 or DAP12 cause Nasu-Hakola disease, which is characterized by bone abnormalities and dementia. Recently, a variant of TREM2 has also been associated with an increased risk for Alzheimer disease. The selective expression of TREM2 on immune cells and its association with different forms of dementia indicate a contribution of this receptor in common pathways of neurodegeneration.

Keywords: Alzheimer disease; cell signaling; microglia; neurodegenerative disease; neuroinflammation; protein processing.

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Figures

FIGURE 1.
FIGURE 1.
TREM2-DAP12 dependent intracellular signaling pathways. TREM2 associates with DAP12 via electrostatic interaction within the transmembrane domains. Ligand binding to TREM2 results in phosphorylation of tyrosine residues within an ITAM motif of the DAP12 cytoplasmic domain, as well as recruitment of several signaling proteins, including Syk, Dok3, Sos1, and Grb2. The related signaling pathways regulate Ca2+ mobilization, cell cytoskeletal remodeling, and gene transcription. The regulation of TREM2-DAP12 via PI3K and RAS allows cross-talk with and modulation of TLR signaling pathways. See text for details. P, phosphorylation; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; LEF, lymphoid enhancer-binding factor; MEF, myocyte enhancer factor; MKK, mitogen-activated protein kinase kinase.
FIGURE 2.
FIGURE 2.
Sequential proteolytic processing of TREM2. The full-length TREM2 receptor (TREM2-FL) can be cleaved by a shedding protease of the ADAM family (sheddase), resulting in the secretion of a soluble ectodomain (sTREM2) and generation of a membrane-bound C-terminal fragment (TREM2-CTF). This C-terminal fragment represents a substrate for γ-secretase-dependent intramembrane proteolysis. The putative cleavage products resulting from γ-secretase-dependent cleavage are indicated as T2β (TREM2-A β-like peptides) and T2ICD (TREM2 intracellular domain). Potential implications of the proteolytic processing for TREM2 function are discussed in the text.
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