WordNet

causing confusion or disorientation; "a confusing jumble of road signs"; "being hospitalized can be confusing and distressing for a small child"
lacking clarity of meaning; causing confusion or perplexity; "sent confusing signals to Iraq"; "perplexing to someone who knew nothing about it"; "a puzzling statement" (同)perplexing, puzzling

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乱混させる[ような],当惑させる

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/26 12:54:09」(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.

English Journal

CXCR4 signaling is controlled by immobilization at the plasma membrane.

Beletkaia E1, Fenz SF2, Pomp W1, Snaar-Jagalska BE3, Hogendoorn PW4, Schmidt T1.
Biochimica et biophysica acta.Biochim Biophys Acta.2016 Apr;1863(4):607-16. doi: 10.1016/j.bbamcr.2015.12.020. Epub 2015 Dec 31.
Understanding of the regulation mechanisms of CXCR4 signaling is essential for revealing its role in physiological and pathological processes. Though biochemical pathways following CXCR4 activation by its ligand CXCL12 are well established, knowledge about the receptor dynamics on the plasma membran
PMID 26748383

Multi-stage inhibition in breast cancer metastasis by orally active triple conjugate, LHTD4 (low molecular weight heparin-taurocholate-tetrameric deoxycholate).

Alam F1, Al-Hilal TA2, Park J3, Choi JU3, Mahmud F1, Jeong JH4, Kim IS2, Kim SY5, Hwang SR6, Byun Y7.
Biomaterials.Biomaterials.2016 Apr;86:56-67. doi: 10.1016/j.biomaterials.2016.01.058. Epub 2016 Feb 8.
Targeting multiple stages in metastatic breast cancer is one of the effective ways to inhibit metastatic progression. To target human metastatic breast cancer as well as improving patient compliance, we developed an orally active low molecular weight heparin (LMWH)-taurocholate conjugated with tetra
PMID 26890038

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

Japanese Journal

翻刻・解題ノートルダム清心女子大学附属図書館黒川文庫蔵『源氏不審抄出』(下)

ノートルダム清心女子大学紀要. 外国語・外国文学編, 文化学編, 日本語・日本文学編 = Notre Dame Seishin University kiyo 38(1), 38-52, 2014
NAID 40020009157

マルチモダリティによる Fusin Imaging 技術について

超音波検査技術 34(4), 482-487, 2009
NAID 80020446540

五感を活用した高臨場感エンタテインメント：ダンスセラピー

横幹連合コンファレンス予稿集 2009(0), 63-63, 2009
NAID 130004651747

「CXCR4 receptor」

Chemokine (C-X-C motif) receptor 4
	CXCR4 in complex with IT1t(PDB 3OE9)
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	2K03, 2K04, 2K05, 3ODU, 3OE0, 3OE6, 3OE8, 3OE9, 4RWS
Identifiers
Symbols	CXCR4 ; CD184; D2S201E; FB22; HM89; HSY3RR; LAP-3; LAP3; LCR1; LESTR; NPY3R; NPYR; NPYRL; NPYY3R; WHIM; WHIMS
External IDs	OMIM: 162643 MGI: 109563 HomoloGene: 20739 IUPHAR: 71 ChEMBL: 2107 GeneCards: CXCR4 Gene
Gene ontology
Molecular function	• virus receptor activity; • actin binding; • G-protein coupled receptor activity; • protein binding; • coreceptor activity; • C-X-C chemokine receptor activity; • cytokine binding; • ubiquitin protein ligase binding; • myosin light chain binding; • ubiquitin binding;
Cellular component	• cytoplasm; • lysosome; • early endosome; • late endosome; • cytosol; • plasma membrane; • cell surface; • integral component of membrane; • cytoplasmic membrane-bounded vesicle; • cell junction; • cell leading edge; • cytoplasmic vesicle; • extracellular exosome;
Biological process	• activation of MAPK activity; • response to hypoxia; • dendritic cell chemotaxis; • apoptotic process; • inflammatory response; • G-protein coupled receptor signaling pathway; • positive regulation of cytosolic calcium ion concentration; • response to virus; • viral process; • calcium-mediated signaling; • entry into host cell; • neutrophil activation; • myelin maintenance; • viral entry into host cell; • positive regulation of oligodendrocyte differentiation; • regulation of chemotaxis; • chemokine-mediated signaling pathway; • cellular response to cytokine stimulus;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;