TYROBP : transmembrane immune signaling adaptor TYROBP
Description
The TYROBP (transmembrane immune signaling adaptor TYROBP) is a protein-coding gene located on chromosome 19.
The TYROBP gene provides instructions for making the TYRO protein tyrosine kinase binding (TYROBP) protein. This protein is found in a variety of cells that are produced in bone marrow (myeloid cells) and other immune system cells (lymphoid cells). The protein is located on the cell surface, where it helps transmit chemical signals that activate the cell. The TYROBP protein interacts with several other proteins on the surface of cells. For example, it forms a complex with the protein produced from the TREM2 gene. The TYROBP protein and its partners were first identified in the immune system, where they activate certain cells (such as natural killer cells and dendritic cells) that trigger an inflammatory response to injury or disease. The TYROBP-TREM2 complex also activates cells in the skeletal system and in the brain and spinal cord (central nervous system). In the skeletal system, the complex is found in osteoclasts, which are specialized cells that break down and remove (resorb) bone tissue that is no longer needed. These cells are involved in bone remodeling, which is a normal process that replaces old bone tissue with new bone. In the central nervous system, the TYROBP-TREM2 complex appears to play an important role in immune cells called microglia. These cells protect the brain and spinal cord from foreign invaders and remove dead nerve cells and other debris. Although the TYROBP-TREM2 complex plays a critical role in osteoclasts and microglia, its exact function in these cells is unclear.
TYROBP (TYRO protein tyrosine kinase-binding protein), also known as DNAX-activation protein 12, Killer-activating receptor-associated protein, is an adapter protein that non-covalently associates with activating receptors on the surface of various immune cells. This association mediates signaling and cell activation upon ligand binding by the receptors. TYROBP undergoes tyrosine phosphorylation in the ITAM domain after ligand binding, activating additional tyrosine kinases and subsequently activating the cell. It also plays an inhibitory role in certain cells. TYROBP associates with activating receptors of the CD300 family, mediating cell activation. It also mediates cell activation through association with activating receptors of the CD200R family. TYROBP is required for neutrophil activation mediated by integrin and for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor. It associates with natural killer (NK) cell receptors like KIR2DS2 and the KLRD1/KLRC2 heterodimer, mediating NK cell activation. TYROBP enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2, and KIR2DS4, ensuring their stability at the cell surface. It associates with SIRPB1 to mediate the activation of myeloid cells like monocytes and dendritic cells. TYROBP associates with TREM1 to activate neutrophils and monocytes. Association with TREM2 on monocyte-derived dendritic cells leads to upregulation of chemokine receptor CCR7, dendritic cell maturation, and survival. TYROBP association with TREM2 mediates cytokine-induced formation of multinucleated giant cells, formed by macrophage fusion. TYROBP stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding, suppressing pro-inflammatory cytokine release. In microglia, TYROBP is required with TREM2 for phagocytosis of apoptotic neurons. It is also required with ITGAM/CD11B in microglia to control the production of microglial superoxide ions, promoting neuronal apoptosis during brain development. TYROBP promotes pro-inflammatory responses in microglia following nerve injury, accelerating the degeneration of injured neurons. It positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells, inhibiting their T cell allostimulatory ability. TYROBP negatively regulates B cell proliferation. It is required for CSF1-mediated osteoclast cytoskeletal organization and positively regulates multinucleation during osteoclast development. {ECO:0000250|UniProtKB:O54885, ECO:0000269|PubMed:10449773, ECO:0000269|PubMed:10604985, ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:15557162, ECO:0000269|PubMed:16920917, ECO:0000269|PubMed:17928527, ECO:0000269|PubMed:18957693, ECO:0000269|PubMed:21727189, ECO:0000269|PubMed:23715743, ECO:0000269|PubMed:25957402, ECO:0000269|PubMed:26221034, ECO:0000269|PubMed:9490415, ECO:0000269|PubMed:9655483}
TYROBP is also known as DAP12, KARAP, PLOSL, PLOSL1.
