F2RL1
Description
The F2RL1 (F2R like trypsin receptor 1) is a protein-coding gene located on chromosome 5.
Protease activated receptor 2 (PAR2), also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11), is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses, obesity, metabolism, cancers and acts as a sensor for proteolytic enzymes generated during infection. In humans, we can find PAR2 in the stratum granulosum layer of epidermal keratinocytes. Functional PAR2 is also expressed by several immune cells such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells.
== Gene == The F2RL1 gene contains two exons and is widely expressed in human tissues. The predicted protein sequence is 83% identical to the mouse receptor sequence.
== Mechanism of activation ==
PAR2 is a member of the large family of 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins. PAR2 is also a member of the protease-activated receptor family. PAR2 is activated by several different endogenous and exogenous proteases. It is activated by proteolytic cleavage of its extracellular amino terminus between arginine and serine.
F2RL1 is a receptor for trypsin and trypsin-like enzymes, coupled to G proteins. Its function is mediated through the activation of several signaling pathways, including phospholipase C (PLC), intracellular calcium, mitogen-activated protein kinase (MAPK), I-kappaB kinase/NF-kappaB, and Rho. It can also be transactivated by cleaved F2R/PAR1. F2RL1 is involved in modulation of inflammatory responses and regulation of innate and adaptive immunity, acting as a sensor for proteolytic enzymes generated during infection. Generally, it promotes inflammation. It can signal synergistically with TLR4 and probably TLR2 in inflammatory responses and modulates TLR3 signaling. F2RL1 has a protective role in establishing the endothelial barrier, with activity involving coagulation factor X. It regulates endothelial cell barrier integrity during neutrophil extravasation, likely following proteolytic cleavage by PRTN3. F2RL1 is proposed to have a bronchoprotective role in airway epithelium but can also compromise the airway epithelial barrier by interrupting E-cadherin adhesion. F2RL1 is involved in the regulation of vascular tone, and its activation results in hypotension, presumably mediated by vasodilation. F2RL1 associates with a subset of G proteins alpha subunits such as GNAQ, GNA11, GNA14, GNA12, and GNA13, but likely not with G(o)-alpha, G(i) subunit alpha-1, and G(i) subunit alpha-2. However, it can signal through G(i) subunit alpha. F2RL1 is believed to be a class B receptor that internalizes as a complex with arrestin and traffics with it to endosomal vesicles, presumably as a desensitized receptor, for extended periods of time. F2RL1 mediates inhibition of TNF-alpha stimulated JNK phosphorylation via coupling to GNAQ and GNA11, involving dissociation of RIPK1 and TRADD from TNFR1. F2RL1 mediates phosphorylation of nuclear factor NF-kappa-B RELA subunit at 'Ser-536', involving IKBKB and is predominantly independent of G proteins. F2RL1 is involved in cellular migration, cytoskeletal rearrangement, and chemotaxis through beta-arrestin-promoted scaffolds, independent of GNAQ and GNA11, involving promotion of cofilin dephosphorylation and actin filament severing. F2RL1 induces redistribution of COPS5 from the plasma membrane to the cytosol, and activation of the JNK cascade is mediated by COPS5. F2RL1 is involved in the recruitment of leukocytes to the sites of inflammation and is the major PAR receptor capable of modulating eosinophil function, such as pro-inflammatory cytokine secretion, superoxide production, and degranulation. During inflammation, F2RL1 promotes dendritic cell maturation, trafficking to the lymph nodes, and subsequent T-cell activation. F2RL1 is involved in the antimicrobial response of innate immune cells, and its activation enhances phagocytosis of Gram-positive and killing of Gram-negative bacteria. It acts synergistically with interferon-gamma in enhancing antiviral responses. F2RL1 is implicated in a number of acute and chronic inflammatory diseases, such as those affecting the joints, lungs, brain, gastrointestinal tract, periodontium, skin, and vascular systems, as well as in autoimmune disorders. F2RL1 interacts with TLR4, COPS5, and TMED2. It also interacts with GNAQ, GNA11, GNA12, GNA13, and GNA14.
F2RL1 is also known as GPR11, PAR2.
