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a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

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=sense organ / 受信装置

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/02 17:35:05」(JST)

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C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the CXCR4 gene.^[1]^[2]

Function

CXCR-4 is an alpha-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12), a molecule endowed with potent chemotactic activity for lymphocytes. CXCR4 is one of several chemokine receptors that HIV can use to infect CD4+ T cells. HIV isolates that use CXCR4 are traditionally known as T-cell tropic isolates. Typically, these viruses are found late in infection. It is unclear as to whether the emergence of CXCR4-using HIV is a consequence or a cause of immunodeficiency.

CXCR4 is upregulated during the implantation window in natural and hormone replacement therapy cycles in the endometrium, producing, in presence of a human blastocyst, a surface polarization of the CXCR4 receptors suggesting that this receptor is implicated in the adhesion phase of human implantation.

CXCR4's ligand SDF-1 is known to be important in hematopoietic stem cell homing to the bone marrow and in hematopoietic stem cell quiescence. Until recently, SDF-1 and CXCR4 were believed to be a relatively monogamous ligand-receptor pair (other chemokines are promiscuous, tending to use several different chemokine receptors). Recent evidence demonstrates ubiquitin is also a natural ligand of CXCR4.^[3] Ubiquitin is a small (76-amino acid) protein highly conserved among eukaryotic cells. It is best known for its intracellular role in targeting ubiquitylated proteins for degradation via the ubiquitin proteasome system. Evidence in numerous animal models suggests ubiquitin is anti-inflammatory immune modulator and endogenous opponent of proinflammatory damage associated molecular pattern molecules.^[4] It is speculated this interaction may be through CXCR4 mediated signalling pathways. MIF is an additional ligand of CXCR4^[5]

CXCR4 is present in newly generated neurons during embryogenesis and adult life where it plays a role in neuronal guidance. The levels of the receptor decrease as neurons mature. CXCR4 mutant mice have aberrant neuronal distribution. This has been implicated in disorders such as epilepsy.^[6]

Clinical significance

Drugs that block the CXCR4 receptor appear to be capable of "mobilizing" hematopoietic stem cells into the bloodstream as peripheral blood stem cells. Peripheral blood stem cell mobilization is very important in hematopoietic stem cell transplantation (as a recent alternative to transplantation of surgically harvested bone marrow) and is currently performed using drugs such as G-CSF. G-CSF is a growth factor for neutrophils (a common type of white blood cells), and may act by increasing the activity of neutrophil-derived proteases such as neutrophil elastase in the bone marrow leading to proteolytic degradation of SDF-1. Plerixafor (AMD3100) is a drug, recently approved for routine clinical use,^[7] which directly blocks the CXCR4 receptor. It is a very efficient inducer of hematopoietic stem cell mobilization in animal and human studies.

It has been associated with WHIM syndrome.^[8] WHIM like mutations in CXCR4 were recently identified in patients with Waldenstrom's macroglobulinemia, a B-cell malignancy.^[9]

While CXCR4’s expression is low or absent in many healthy tissues, it was demonstrated to be expressed in over 23 types of cancer, including breast cancer, ovarian cancer, melanoma, and prostate cancer. Expression of this receptor in cancer cells has been linked to metastasis to tissues containing a high concentration of CXCL12, such as lungs, liver and bone marrow.^[10]^[11] However, in breast cancer where SDF1/CXCL12 is also expressed by the cancer cells themselves along with CXCR4, CXCL12 expression is positively correlated with disease free (metastasis free) survival. CXCL12 (over-)expressing cancers might not sense the CXCL12 gradient released from the metastasis target tissues since the receptor, CXCR4, is saturated with the ligand produced in an autocrine manner.^[12] Another explanation of this observation is provided by a study that shows the ability of CXCL12 (and CCL2) producing tumors to entrain neutrophils that inhibit seeding of tumor cells in the lung.^[13]

Drug response

Chronic exposure to THC has been shown to increase T lymphocyte CXCR4 expression on both CD4+ and CD8+ T lymphocytes in rhesus macaques.^[14]

Interactions

CXCR4 has been shown to interact with USP14.^[15]

References

^ Moriuchi M, Moriuchi H, Turner W, Fauci AS (Nov 1997). "Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry". Journal of Immunology 159 (9): 4322–9. PMID 9379028.
^ Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, Parmentier M, Arenzana-Seisdedos F (Apr 1998). "Genomic organization and promoter characterization of human CXCR4 gene". FEBS Letters 426 (2): 271–8. doi:10.1016/S0014-5793(98)00359-7. PMID 9599023.
^ Saini V, Marchese A, Majetschak M (May 2010). "CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin". The Journal of Biological Chemistry 285 (20): 15566–76. doi:10.1074/jbc.M110.103408. PMC 2865327. PMID 20228059.
^ Majetschak M (Feb 2011). "Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules". Journal of Leukocyte Biology 89 (2): 205–19. doi:10.1189/jlb.0510316. PMID 20689098.
^ Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L, Kooistra T, Fingerle-Rowson G, Ghezzi P, Kleemann R, McColl SR, Bucala R, Hickey MJ, Weber C (May 2007). "MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment". Nature Medicine 13 (5): 587–96. doi:10.1038/nm1567. PMID 17435771.
^ Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M, Pleasure SJ (Sep 2002). "The chemokine SDF1 regulates migration of dentate granule cells". Development 129 (18): 4249–60. PMID 12183377.
^ To LB, Levesque JP, Herbert KE (Oct 2011). "How I treat patients who mobilize hematopoietic stem cells poorly". Blood 118 (17): 4530–40. doi:10.1182/blood-2011-06-318220. PMID 21832280.
^ Balabanian K, Levoye A, Klemm L, Lagane B, Hermine O, Harriague J, Baleux F, Arenzana-Seisdedos F, Bachelerie F (Mar 2008). "Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling". The Journal of Clinical Investigation 118 (3): 1074–84. doi:10.1172/JCI33187. PMC 2242619. PMID 18274673.
^ Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP (Mar 2014). "The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis". Blood 123 (11): 1637–46. doi:10.1182/blood-2013-09-525808. PMID 24366360.
^ Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ, Wang J (Dec 2010). "CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression". Cancer Metastasis Reviews 29 (4): 709–22. doi:10.1007/s10555-010-9256-x. PMC 3175097. PMID 20839032.
^ Balkwill F (Jul 2004). "Cancer and the chemokine network". Nature Reviews. Cancer 4 (7): 540–50. doi:10.1038/nrc1388. PMID 15229479.
^ Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U (Sep 2009). "CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival". European Journal of Cancer 45 (14): 2579–87. doi:10.1016/j.ejca.2009.06.026. PMID 19646861.
^ Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (Sep 2011). "Tumor entrained neutrophils inhibit seeding in the premetastatic lung". Cancer Cell 20 (3): 300–14. doi:10.1016/j.ccr.2011.08.012. PMC 3172582. PMID 21907922.
^ LeCapitaine NJ, Zhang P, Winsauer P, Walker E, Vande Stouwe C, Porretta C, Molina PE (Dec 2011). "Chronic Δ-9-tetrahydrocannabinol administration increases lymphocyte CXCR4 expression in rhesus macaques". Journal of Neuroimmune Pharmacology 6 (4): 540–5. doi:10.1007/s11481-011-9277-4. PMC 3181271. PMID 21484257.
^ Mines MA, Goodwin JS, Limbird LE, Cui FF, Fan GH (Feb 2009). "Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation". The Journal of Biological Chemistry 284 (9): 5742–52. doi:10.1074/jbc.M808507200. PMC 2645827. PMID 19106094.

External links

"Chemokine Receptors: CXCR4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

UpToDate Contents

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1. 複合免疫不全 combined immunodeficiencies
2. 白血球増多症および好中球増多症の定義およびメカニズム definition and mechanisms of leukocytosis and neutrophilia
3. HIV-1感染の免疫学 immunology of hiv 1 infection
4. 造血幹細胞の分布 sources of hematopoietic stem cells
5. 免疫系に対するステロイドの影響 glucocorticoid effects on the immune system

English Journal

Cell migration towards CXCL12 in leukemic cells compared to breast cancer cells.

Mills SC1, Goh PH1, Kudatsih J1, Ncube S1, Gurung R1, Maxwell W1, Mueller A2.
Cellular signalling.Cell Signal.2016 Apr;28(4):316-24. doi: 10.1016/j.cellsig.2016.01.006. Epub 2016 Jan 21.
Chemotaxis or directed cell migration is mediated by signalling events initiated by binding of chemokines to their cognate receptors and the activation of a complex signalling cascade. The molecular signalling pathways involved in cell migration are important to understand cancer cell metastasis. Th
PMID 26806619

PLZF-Induced Upregulation of CXCR4 Promotes Dairy Goat Male Germline Stem Cell Proliferation by Targeting Mir146a.

Mu H1, Li N1, Wu J1,2, Zheng L1, Zhai Y1, Li B1, Song W1, Wang J1, Zhu H1,3, Li G4, Hua J1.
Journal of cellular biochemistry.J Cell Biochem.2016 Apr;117(4):844-52. doi: 10.1002/jcb.25371. Epub 2015 Oct 23.
Previous studies have shown that promyelocytic leukemia zinc finger (PLZF), chemokine (C-X-C motif) receptor 4 (CXCR4) and mir146a were associated with the self-renewal of mouse spermatogonial stem cells (SSCs); however, there is little information on their effects on the fate of livestock SSCs. Her
PMID 26365432

No evidence for cell activation or brain vaso-occlusion with plerixafor mobilization in sickle cell mice.

Choi E1, Branch C2, Cui MH2, Yazdanbakhsh K1, Mohandas N1, Billett HH3, Shi PA4.
Blood cells, molecules & diseases.Blood Cells Mol Dis.2016 Mar;57:67-70. doi: 10.1016/j.bcmd.2015.12.008. Epub 2015 Dec 21.
Gene therapy for sickle cell disease is currently in active trials. Collecting hematopoietic progenitor cells safely and effectively is challenging, however, because granulocyte colony stimulating factor, the drug used most commonly for mobilization, can cause life-threatening vaso-occlusion in pati
PMID 26852658

Japanese Journal

3) 卵巣癌腹膜播種の分子機構に関する複合的機能解析と新規治療戦略(シンポジウム1:腫瘍「婦人科癌の浸潤・転移機構の解明と臨床応用」,第65回日本産科婦人科学会・学術講演会講演要旨)

柴田清住
日本産科婦人科學會雜誌 65(10), 2414-2425, 2013-10-01
… In addition, we assessed the inhibitory effects of AMD3100, a neutralizing antibody against chemokine receptor (CXCR4). …
NAID 110009674403

C-X-C chemokine receptor type 4 and cytokine expressions in cows of a dairy herd with high prevalence of calves persistently infected with bovine viral diarrhea virus

Helal Mahmoud Atef Youssef,Hoshino Yuki,Takagi Satoshi,Tajima Motoshi
Japanese Journal of Veterinary Research 61(3), 109-116, 2013-08
… Alteration of maternal C-X-C chemokine receptortype 4 (CXCR4) expression has been suspected as closely concerned with the production ofPI calves. … It is not clear what the influence of CXCR4 response to the prevalence of PIcalves. … CXCR4 and cytokine expressions in cowsof this herd were investigated. … There were no significant differences in CXCR4 andcytokine expressions between the dams of PI calves and the dams of non PI calves in theherd. …
NAID 120005322437

X4-tropic human immunodeficiency virus ⅢB utilizes CXCR4 as coreceptor, as distinct from R5X4-tropic viruses

Islam Salequl,Hoque Sheikh Ariful,Adnan Nihad [他]
Microbiology and immunology 57(6), 437-444, 2013-06
NAID 40019700918

「CXCR4受容体」

CXCR4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4RWS, 2K03, 2K04, 2K05, 3ODU, 3OE0, 3OE6, 3OE8, 3OE9, 2N55
Identifiers
Aliases	CXCR4, CD184, D2S201E, FB22, HM89, HSY3RR, LAP-3, LAP3, LCR1, LESTR, NPY3R, NPYR, NPYRL, NPYY3R, WHIM, WHIMS, C-X-C motif chemokine receptor 4
External IDs	OMIM: 162643 MGI: 109563 HomoloGene: 20739 GeneCards: 7852
Gene ontology
Molecular function	• cytokine binding; • coreceptor activity; • virus receptor activity; • signal transducer activity; • protein binding; • chemokine receptor activity; • drug binding; • myosin light chain binding; • actin binding; • ubiquitin protein ligase binding; • ubiquitin binding; • C-X-C chemokine receptor activity; • G-protein coupled receptor activity;
Cellular component	• cytoplasm; • integral component of membrane; • endosome; • membrane; • cytoplasmic, membrane-bounded vesicle; • cell surface; • cell junction; • cell leading edge; • extracellular exosome; • cytoplasmic vesicle; • early endosome; • late endosome; • lysosome; • plasma membrane;
Biological process	• myelin maintenance; • positive regulation of oligodendrocyte differentiation; • epithelial cell development; • regulation of programmed cell death; • regulation of calcium ion transport; • regulation of cell migration; • response to hypoxia; • cardiac muscle contraction; • regulation of chemotaxis; • positive regulation of cytosolic calcium ion concentration; • chemokine-mediated signaling pathway; • response to virus; • neuron migration; • dendritic cell chemotaxis; • cellular response to cytokine stimulus; • telencephalon cell migration; • chemotaxis; • neuron recognition; • activation of MAPK activity; • inflammatory response; • cell migration; • calcium-mediated signaling; • entry into host cell; • signal transduction; • apoptotic process; • viral process; • fusion of virus membrane with host plasma membrane; • G-protein coupled receptor signaling pathway;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ; ; ;
	More reference expression data
Orthologs
	7852
	12767
	ENSG00000121966
	ENSMUSG00000045382
	P61073
	P70658
	NM_003467; NM_001008540
	NM_009911
	NP_001008540.1; NP_003458.1
	NP_034041.2
	Wikidata
View/Edit Human	View/Edit Mouse