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FLASH GENE

Symbol

CXCR4

contributors: mct/pgu - updated : 12-09-2016

HGNC name	chemokine (C-X-C motif) receptor 4
HGNC id	2561

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

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 heart         Digestive stomach         Endocrine neuroendocrine pituitary     highly Lymphoid/Immune lymph node       highly   spleen       highly Nervous brain forebrain cerebral cortex       spinal cord         Respiratory lung         Visual eye retina       Rattus norvegicus

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining retinal pigment epithelium (RPE)     Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic leukocyte Lymphoid/Immune dendritic cell Lymphoid/Immune macrophage Visual epithelial cell

cell lineage	the more immature CD34+ hematopoietic stem cells, in platelets
cell lines	breast cancer cell lines
fluid/secretion

at STAGE

physiological period

embryo

Text	developping vascular endothelial cells

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	seven transmembrane segments (7TM), with only five transmembrane domain chemokine receptors
	two potential N-glycosylation sites
	three intracellular loop (ICL1, ICL2, ICL3), ICL2 and ICL3 are involved in JAK2 and STAT3 phosphorylation

secondary structure	intracellular loop 1 (ICL1, AAs 65 to 71) linking helices I and II; ICL2 (AAs 140 to 144) linking helices III and IV; ICL3 (AAs 225 to 230) linking helices V and VI; and the C terminus (ICL3 also contains T4L inserted between Ser229 and Lys230 and flanked by short linkers (GS-T4L-GS))

HOMOLOGY

Homologene

FAMILY

G protein coupled receptor 1 family

CATEGORY

signaling , receptor membrane G

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,organelle,lysosome

basic FUNCTION	regulates hematopoietic and tumor cell homing to bone
	mediating migration of resting leukocytes and hematopoietic progenitors in response to SDF
	required for entry of T cell line-tropic strains HIV-1 into CD4 cells
	playing a role of receptor for SDF1 to directing the primordial germ cell migration
	allows cells to migrate in response to a gradient of chemokine ligands
	playing also an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodelling processes in endothelial cells
	important for maturation and survival of dendritic cells to initiate acquired immune response
	may be involved in a general mechanism in the regulation of hematopoiesis, linking lineage-specific transcription factors, miRNAs and key mRNA targets, particularly growth factor/chemokine receptors
	during human T cell activation by antigen-presenting cells, recruited into the immunological synapse, where they deliver costimulatory signals
	activation of CXCR4 results in a direct negative inotropic modulation of cardiac myocyte function
	promotes metastasis by preventing anoikis in cancer cells
	may be involved in the maturation of bone marrow-derived dendritic cells, which is regulated by notch signaling
	forms functional complexes with CD74 that mediate MIF-specific signaling
	fucntional receptor for extracellular ubiquitin
	critical regulator of oligodendrocyte precursor cells (OPCs) remyelination within damaged white matter of the adult CNS
	CXCR4 and the related CCR5 serve as co-receptors for HIV-1 viral particles, facilitating their entry into cells
	CXCL12/CXCR4 system is involved in modulation of nociceptive signalling
	its signaling regulates radial glial morphology and cell fate during embryonic spinal cord development
	prevents dispersion of granule neuron precursors in the adult dentate gyrus
	CXCL12/CXCR4 signal axis plays an important role in mediating BMP9-induced osteogenic differentiation of mesenchymal stem cells
	CXCR4 signaling also modulates synaptic function and neuronal survival in the mature brain, through direct and indirect effects on neurons and glia

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures

a component	SDF1/CXCR4 signaling playing a role in the development of migrating muscle progenitors and a threshold number of progenitor cells is required to generate muscle of appropriate size
	part of AIP4.arrestin-2 complex that functions on endosomes to regulate sorting of CXCR4 into the degradative pathway
	crucial regulatory axis for the ventral axonal trajectory of developing spinal MNs, consisting of the ISL1-LHX3 complex, STAM1 and CXCR4

INTERACTION

DNA

RNA

small molecule	other,
	dietary antioncogene cumin repressing CXCR4 expression

protein	ligand of CXCL12 (to transduce CXCL12 -mediated chemotaxis)
	interaction between CXCR4 and CCR5 to exert specific biological functions and modulate T lymphocyte responses, and cooperation between receptors represents one key strategy for the functional plasticity of chemokines
	SYT3 is essential for CXCR4 recycling in T cells and thereby for the maintenance of high CXCR4 surface levels required for migration)
	interact with PLEC (PLEC plays an important role in CXCR4 signaling and trafficking and HIV-1 infection)
	interacting with MIF and CD74 (CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling)
	molecular link between UBE2I and the metastasis genes such as CDC42 and CXCR4, and thus provide new insight into the mechanism by which UBE2I9 promotes tumor invasion and metastasis
	CCL18 is an important modulator of CXCR4-dependent responses in pre-B ALL cells via interactions with GPR30 (PMIDS:
	both ACKR3 and CXCR4 are important for endothelial progenitor cells (EPCs) in response to CXCL12
	ACKR3 may interact with CXCR4 at the intracellular level, possibly affecting CXCR4 trafficking and/or coupling to other proteins
	PLG regulates MMP9-dependent CXCR4 expression to facilitate hematopoietic progenitor and stem cell (HPSC) mobilization in response to CSF3
	coordinated changes in CXCR4 and S1PR5 responsiveness govern NK-cell trafficking
	HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4
	KLF11 regulates the expression of CXCR4 at a specific KLF11 binding site
	CXCL12 protects neural progenitor cells (hNPCs) from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling
	NOTCH1 signaling regulates CXCR4 expression and the migration of mesenchymal stem cells
	DEFB103B can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation
	CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12-CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses
	ACKR3 potentiates CXCR4 response and may contribute to the maintenance of leukemia by initiating cell recruitment to bone marrow niches that were once occupied by normal hematopoietic stem cells
	MIF promotes the migration of B cells through a ZAP70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74
	novel role for the really interesting new gene-domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes
	addition of CXCL12 leads to the dissociation of EIF2S2 from CXCR4 suggesting that stimulation of the receptor may trigger the local protein synthesis required for efficient cell movement
	RGS1 desensitizes the chemokine receptors CCR7 and CXCR4 that are critical to the localization of T and B cells in lymphoid organs
	GNG4 is an inhibitor of CXCL12/CXCR4-dependent signaling
	link between the ECM protein MATN4 and cytokine receptor CXCR4 involved in the regulation of hematopoietic stem cells (HSCs) proliferation and expansion under acute stress
	ARRB1 and STAM cooperate to promote focal adhesion kinase autophosphorylation and chemotaxis via the chemokine receptor CXCR4
	NRF1 regulates likely the expression of CXCR4 in normal retinal development and in pathologic processes of retinal hypoxia and neovascularization
	HCLS1 is important for the activation of GTPases and integrins, and mediates signaling downstream of many receptors including BCR, TCR, and CXCR4

cell & other

REGULATION

activated by

ZBTB16 in megakaryopoiesis

induced by	NFKB to promoting breast cancer cell migration and metastasis
		CXCL12 (increased the mRNA and surface expression of CXCR4 receptor in synovial fibroblasts)

inhibited by

VHL

Other	regulated by YY1
	USP8 is a positive regulator of CXCR4 trafficking for degradation

ASSOCIATED DISORDERS

corresponding disease(s)

WHIM

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in breast cancer cells, malignant breast tumor and metastases tumoral     --over   in metastatic renal clear cell carcinoma constitutional     --other   aberrantly expressed in pathological specimens of vitreoretinal membranes tumoral     --over   in melanoma cells in primary lesions, significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate constitutional       loss of function enhances osteoclastogenesis, and may enhance established skeletal tumor burden by increasing osteoclasts activity constitutional     --over   with CXCL12 in patients with heart failure constitutional       gain of function CXCR4 activation, by promoting the differentiation of oligodendrocyte precursor cells into oligodendrocytes, is critical for remyelination of the injured adult CNS tumoral     --over   significantly associated with lymph node status and distant metastasis and indicated poor overall and disease free survival

Susceptibility

to leukocyte telomere length

Variant & Polymorphism SNP	rs4452212 associated with variation of leukocyte telomere length

Candidate gene	use of CXCR4 inhibitors, particularly in patients with bone metastases
	presence of functional CXCR4 on cardiac myocytes introduces a new target for treating cardiac dysfunction
	useful prognostic factor for patients with metastatic prostate cancer treated with androgen-withdrawal therapy
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous hypertension   CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure

ANIMAL & CELL MODELS

diminished Cxcr4 alters interneuron migration in Large Deletion (LgDel) 22q11.2DS mice