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FLASH GENE

Symbol

F2R

contributors: mct - updated : 18-01-2017

HGNC name	coagulation factor II (thrombin) receptor
HGNC id	3537

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	5q13.3      Physical location : 76.011.867 - 76.031.594
Synonym name	thrombin receptor, proteinase activated receptor 1
	protease-activated receptor-1
Synonym symbol(s)	TRBR, PAR1, CF2R, TR, HTR, PAR

DNA

TYPE	functioning gene
STRUCTURE	19.73 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   HRE
text structure	functional androgen response element (ARE) located in the promoter upstream of the transcription start site at -1791 to -1777

MAPPING

cloned

Y

linked

status

confirmed

Map

see F2RL1

regionally located

centrometric to the common proximal breakpoint

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001992 2 - 3847 NP_001983 - 425 - 2001 11533492 NM_001311313 3 - 3942 NP_001298242 - 304 - 2001 11533492

EXPRESSION

Rna function	mRNA appears to be expressed by a subset of neurons, including granule cells in the dentate gyrus
Type	widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       highly Homo sapiens Digestive intestine         Homo sapiens Lymphoid/Immune spleen       moderately Nervous brain limbic system hippocampus dentate gyrus highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic platelet Homo sapiens Cardiovascular endothelial cell Homo sapiens Digestive enterocyte Homo sapiens Lymphoid/Immune lymphocyte Homo sapiens Lymphoid/Immune macrophage Nervous astrocyte Homo sapiens Nervous glia Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

seven transmembrane segments (7TM) receptor

mono polymer

heteromer , dimer

HOMOLOGY

Homologene

FAMILY	G protein coupled receptor superfamily
	PAR family

CATEGORY

protooncogene , receptor membrane G

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,endosome

basic FUNCTION	high activity receptor for activated thrombin
	modulate endothelial cell, function in developing blood vessels
	involved in the invasive phase of placentation
	involved in STAT protein nuclear translocation
	involved in the invasive and metastatic processes of various cancers
	distinct roles of F2R, F2RL1 in signal transduction regulation of endothelial nitric oxide synthase
	PROC induces F2R phosphorylation and desensitizes endothelial cells to thrombin signaling but promotes limited receptor cleavage and negligible internalization and degradation even after prolonged PROC exposure
	in microglia may be involved in the regulation of inflammatory reactions modulating the balance between pro- and anti-inflammatory cytokines possibly through SOCS induction
	plays critical roles in cancer, angiogenesis, inflammation, and thrombosis
	involved in a PAR1-dependent Ca2+ signals and migration
	plays a role in malignant and physiological invasion processes
	in gastric carcinoma cells, its activation can trigger an array of responses that would promote tumor cell growth and invasion
	its activation during normal function or pathological conditions, such as during ischemia or hemorrhage, can increase the excitability of dentate granule cells
	its activation promotes EPN1 de-ubiquitination, which may increase its endocytic adaptor activity to facilitate receptor internalization
	F2R and F2RL3 stimulate different signaling pathways in platelets and likely cooperate to mediate the complete response of the platelets to thrombin
	has a role in remodelling the vasculature in the small intestine
	displays constitutive and agonist-induced internalization
	critical and novel role for the coagulation cascade, mediated in part by thrombin-F2R interaction, and regulates hematopoietic stem cells (HSCs) maintenance and a reciprocal interplay between HSCs and the dynamic bone structure
	in addition to desensitization, internalization and lysosomal sorting of activated F2R are critical for the termination of signaling
	contributes to leukemic stem cell maintenance
	F2R-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells
	F2R signaling pathway contributes to epileptogenesis following status epilepticus (SE)
	key role for F2R during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators

CELLULAR PROCESS	cell life, cell death/apoptosis
	cell migration & motility

PHYSIOLOGICAL PROCESS

coagulation/hemostasis , development , inflammation

text	angiogenesis
	morphogenesis

PATHWAY

metabolism

signaling

KLK6-signaling axis in CNS neurons that is mediated by F2R and F2RL1 and is positioned to contribute to neurodegeneration

a component	F2R and F2RL1 form a heterodimer that exhibits unique trafficking and signaling behaviors compared with receptor protomers
	role for F8 and thrombin/F2R in regulating hematopoiesis and its interplay with the bone structure
	undergoing proteolytic irreversible activation by coagulant and anti-coagulant proteases
	MMP1/F2R axis may play a role in neurogenesis following physiological and/or pathological stimuli

INTERACTION

DNA

RNA

small molecule

protein	thrombin
	coupled to calcium, ERK, and AKT signaling (modulating growth in native lens tissue and cultured cells)
	F2R stimulation upregulates the expression of the suppressor of cytokine signaling-3 (SOCS3)
	interacting with EDG3, SPHK1 (signaling controls dissemination of inflammation from the lymphatics)
	BICD1 is a direct interactor with the C-terminal cytoplasmic domain of F2R
	link between F2R signal termination and internalization through the non-G protein effector, BICD1
	F2R and F2RL3 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity
	occupancy of PROCR by its natural ligand modulates the F2R-dependent signaling specificity of coagulation proteases
	MMP1 is an important activator of F2R in sepsis
	interaction between F2R and F2RL3, F2RL3 also interacts with the P2Y12 receptor on platelets to alter signaling
	interacting with GZMK (extracellular GZMK is capable of activating F2R and inducing fibroblast cytokine secretion and proliferation)
	interacting with EPN1 (adaptor protein complex-2 and EPN1 are both critical mediators of agonist-stimulated F2R internalization)
	thrombin activates platelets by binding and cleaving protease-activated receptors F2R and F2RL3
	F3 mediates signalling through coagulation proteases that activate the G-protein-coupled receptors F2R and F2RL1
	MMP1 is a collagenase and activator of the G protein-coupled protease activated receptor-1 (F2R)
	PDCD6IP binds to F2R, recruits ESCRT-III, and mediates receptor sorting to intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)/lysosomes
	AP3B1 facilitates F2R interaction with PDCD6IP, suggesting that AP3B1 functions before F2R engagement of PDCD6IP and multivesicular bodies (MVBs)/lysosomes sorting
	F3 participates in protease-activated receptor F2R and F2RL1 activation
	correlation between F2R and FGFR1 suggests an association of the two receptors with a more aggressive breast cancer phenotype and, consequently, a potential role during tumor progression
	thrombin binds to and cleaves the N terminus of F2R, generating a new N terminus that functions as a tethered ligand that cannot diffuse away
	TFAP2A regulates activated F2R signaling by altering receptor surface expression and through recruitment of regulator of G protein signaling (RGS) proteins
	RAB11B is a critical regulator of F2R trafficking
	RAB11A and RAB11B differentially regulate intracellular trafficking of PAR1 through distinct endosomal sorting mechanisms
	F2R agonist is MMP1
	thrombin upregulates LCN2 through F2R activation and causes brain damage in brain injury
	KLK6-F2R-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease

cell & other

REGULATION

activated by	proteases (including thrombin) proteolytic cleavage of its extracellular N terminus, generating a new receptor N terminus which functions as a tethered ligand and activates the receptor
	MMP1 (cleaving the receptor at the proper site to generate PAR1-dependent Ca2+ signals and migration)
	cleaved and activated by thrombin and other extracellular proteases which are released during tissue trauma and inflammation

Other	regulated transcriptionally by androgens
	regulated by F2RL1 (F2RL1 regulates the F2R hyperplastic response to arterial injury leading to stenosis)
	palmitoylation of F2R regulates appropriate utilization of tyrosine-based motifs by adaptor proteins and endocytic trafficking, processes that are critical for maintaining appropriate expression of F2R at the cell surface

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in prostate cancer progression in androgen-dependent and -independent phases tumoral     --over   in blasts from acute myeloid leukemia, and in chronic myeloid leukemia patients in blast phase

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed immunology infectious   therapeutics that target MMP1-F2R may prove beneficial in the treatment of sepsis cancer digestive stomach potentially important therapeutic target for the treatment of gastric cancer.

ANIMAL & CELL MODELS