同: CXCR4, Fusin, LESTR, NPY3R, HM89

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/03/24 19:13:20」(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. The structure of CXCR4 in complex with CXCL12 was elucidated in;^[3] the computationally derived CXCL12 : CXCR4 complex structure is in remarkable agreement with experimental findings and sheds light into the functional role of CXCL12 and CXCR4 residues which are associated with binding and signaling. CXCR4 is one of several chemokine receptors that HIV can use to infect CD4+ T cells. The molecular recognition of CXCR4 is predominantly mediated through the V3 loop fragment of HIV protein gp120. A computationally derived structure of CXCR4 in complex with a dual HIV-1 gp120 V3 loop was reported in.^[4] The structure is in remarkable agreement with previous experimental findings and sheds light into the role of HIV-1 and CXCR4 residues which are associated with HIV-1 coreceptor activity. 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.^[5] 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.^[6] It is speculated this interaction may be through CXCR4 mediated signalling pathways. MIF is an additional ligand of CXCR4^[7]

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.^[8]

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,^[9] 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.^[10] WHIM like mutations in CXCR4 were recently identified in patients with Waldenstrom's macroglobulinemia, a B-cell malignancy.^[11]

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.^[12]^[13] 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.^[14] 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.^[15]

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.^[16]

Interactions

CXCR4 has been shown to interact with USP14.^[17]

References

^ Moriuchi M, Moriuchi H, Turner W, Fauci AS (November 1997). "Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry". J. Immunol. 159 (9): 4322–9. PMID 9379028. CS1 maint: Date and year (link)
^ Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL et al. (April 1998). "Genomic organization and promoter characterization of human CXCR4 gene". FEBS Lett. 426 (2): 271–8. doi:10.1016/S0014-5793(98)00359-7. PMID 9599023. CS1 maint: Date and year (link)
^ Tamamis P, Floudas CA (April 2014). "Elucidating a key component of cancer metastasis: CXCL12 (SDF-1α) binding to CXCR4". J Chem Inf Model 54 (4): 1174–88. doi:10.1021/ci500069y. PMC 4004218. PMID 24660779. CS1 maint: Date and year (link)
^ Tamamis P, Floudas CA (September 2013). "Molecular recognition of CXCR4 by a dual tropic HIV-1 gp120 V3 loop". Biophys. J. 105 (6): 1502–14. doi:10.1016/j.bpj.2013.07.049. PMC 3785887. PMID 24048002. CS1 maint: Date and year (link)
^ Saini V, Marchese A, Majetschak M (May 2010). "CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin". J. Biol. Chem. 285 (20): 15566–76. doi:10.1074/jbc.M110.103408. PMC 2865327. PMID 20228059. CS1 maint: Date and year (link)
^ Majetschak M (August 2010). "Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules". J. Leukoc. Biol. 89 (2): 205–19. doi:10.1189/jlb.0510316. PMID 20689098. Check date values in: |year= / |date= mismatch (help)
^ Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR et al. (2007). "MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment". Nat. Med. 13 (5): 587–96. doi:10.1038/nm1567. PMID 17435771.
^ Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M et al. (September 2002). "The chemokine SDF1 regulates migration of dentate granule cells". Development 129 (18): 4249–60. PMID 12183377. CS1 maint: Date and year (link)
^ To LB, Levesque JP, Herbert KE (October 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. CS1 maint: Date and year (link)
^ Balabanian K, Levoye A, Klemm L, Lagane B, Hermine O, Harriague J et al. (March 2008). "Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling". J. Clin. Invest. 118 (3): 1074–84. doi:10.1172/JCI33187. PMC 2242619. PMID 18274673. CS1 maint: Date and year (link)
^ Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y et al. (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 et al. (December 2010). "CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression". Cancer Metastasis Rev. 29 (4): 709–22. doi:10.1007/s10555-010-9256-x. PMC 3175097. PMID 20839032. CS1 maint: Date and year (link)
^ Balkwill F (July 2004). "Cancer and the chemokine network". Nat. Rev. Cancer 4 (7): 540–50. doi:10.1038/nrc1388. PMID 15229479. CS1 maint: Date and year (link)
^ Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A et al. (September 2009). "CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival". Eur. J. Cancer 45 (14): 2579–87. doi:10.1016/j.ejca.2009.06.026. PMID 19646861. CS1 maint: Date and year (link)
^ Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (September 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. CS1 maint: Date and year (link)
^ LeCapitaine NJ, Zhang P, Winsauer P, Walker E, Vande Stouwe C, Porretta C et al. (2011). "Chronic Δ-9-tetrahydrocannabinol administration increases lymphocyte CXCR4 expression in rhesus macaques". J Neuroimmune Pharmacol 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 (February 2009). "Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation". J. Biol. Chem. 284 (9): 5742–52. doi:10.1074/jbc.M808507200. PMC 2645827. PMID 19106094. CS1 maint: Date and year (link)

External links

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

English Journal

AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell -based microenvironment: preclinical evidence for its association with chronic lymphocytic leukemia treatments.

Stamatopoulos B, Meuleman N, De Bruyn C, Pieters K, Mineur P, Le Roy C, Saint-Georges S, Varin-Blank N, Cymbalista F, Bron D, Lagneaux L.SourceJules Bordet Institute (ULB), Belgium;
Haematologica.Haematologica.2011 Nov 4. [Epub ahead of print]
Background. Interactions with the microenvironment, such as bone marrow mesenchymal stromal cells and nurse-like cells, protect chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis. This protection is partially mediated by the chemokine SDF-1α (CXCL12) and its receptor CXC
PMID 22058221

Increased levels of circulating SDF-1α and CD34+ CXCR4+ cells in patients with moyamoya disease.

Ni G, Liu W, Huang X, Zhu S, Yue X, Chen Z, Chen M, Liu X, Xu G.SourceDepartment of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu Province, China.
European journal of neurology : the official journal of the European Federation of Neurological Societies.Eur J Neurol.2011 Nov;18(11):1304-9. doi: 10.1111/j.1468-1331.2011.03393.x. Epub 2011 Mar 24.
BACKGROUND AND PURPOSE: Recent studies reported that peripheral blood CD34(+) cells and endothelial progenitor cells contributed to angiogenesis in patients with moyamoya disease (MMD), and stromal cell-derived factor-1α (SDF-1α) modulated angiogenesis by interacting with corresponding CXCR4 recep
PMID 21435112

Related Pictures

2013 broderie maalem turqoise Cd184 replacement element (cd184) (AF-M8037 Human CD184 (CXCR4) PE-Cy5. View More -Engine-Crankshaft-Timing-Belt-CD184 Data for Anti-Mouse CD184 (CXCR4) PE. Condolence Wreath › Eternal Moment CD184 Data for Anti-Human CD184 (CXCR4) PE. Bolero CD184-CM Wooden Side Chair image

★リンクテーブル★

リンク元	「fusin」
関連記事	「CD1」

「fusin」

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
Identifiers
Symbols	CXCR4 ; CD184; D2S201E; FB22; HM89; HSY3RR; LAP-3; LAP3; LCR1; LESTR; NPY3R; NPYR; NPYRL; NPYY3R; WHIM
External IDs	OMIM: 162643 MGI: 109563 HomoloGene: 20739 IUPHAR: CXCR4 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; • plasma membrane; • external side of plasma membrane; • cell surface; • integral component of membrane; • cytoplasmic membrane-bounded vesicle; • cell junction; • growth cone; • cell leading edge; • cytoplasmic vesicle; • extracellular vesicular exosome;
Biological process	• activation of MAPK activity; • patterning of blood vessels; • response to hypoxia; • ameboidal cell migration; • neuron migration; • dendritic cell chemotaxis; • apoptotic process; • inflammatory response; • G-protein coupled receptor signaling pathway; • positive regulation of cytosolic calcium ion concentration; • germ cell development; • brain development; • motor neuron axon guidance; • germ cell migration; • response to virus; • viral process; • calcium-mediated signaling; • entry into host cell; • regulation of cell migration; • T cell proliferation; • neutrophil activation; • myelin maintenance; • positive regulation of oligodendrocyte differentiation; • regulation of chemotaxis; • neural precursor cell proliferation; • chemokine-mediated signaling pathway; • cellular response to cytokine stimulus;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

　　[★]

フーシン

関: CXCR4 receptor

同: CD184

「CD1」

　　[★]

同: leucine-6, CD1A through E

種類

CD1a, CD1b, CD1c, CD1d

発現組織

胸腺皮質、ランゲルハンス細胞、樹状細胞、B細胞(CD1c)、腸上皮、平滑筋、血管上皮(CD1d)

分子量

43-49

機能

MHC class I-like molecule, associated with β2-microgloulin. Has specialized role in presentation of lipid antigens

[pmid9379028-1] Moriuchi M, Moriuchi H, Turner W, Fauci AS (November 1997). "Cloning and analysis of the promoter region of CXCR4, a coreceptor for HIV-1 entry". J. Immunol. 159 (9): 4322–9. PMID 9379028. CS1 maint: Date and year (link)

[pmid9599023-2] Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL et al. (April 1998). "Genomic organization and promoter characterization of human CXCR4 gene". FEBS Lett. 426 (2): 271–8. doi:10.1016/S0014-5793(98)00359-7. PMID 9599023. CS1 maint: Date and year (link)

[pmid24660779-3] Tamamis P, Floudas CA (April 2014). "Elucidating a key component of cancer metastasis: CXCL12 (SDF-1α) binding to CXCR4". J Chem Inf Model 54 (4): 1174–88. doi:10.1021/ci500069y. PMC 4004218. PMID 24660779. CS1 maint: Date and year (link)

[pmid24048002-4] Tamamis P, Floudas CA (September 2013). "Molecular recognition of CXCR4 by a dual tropic HIV-1 gp120 V3 loop". Biophys. J. 105 (6): 1502–14. doi:10.1016/j.bpj.2013.07.049. PMC 3785887. PMID 24048002. CS1 maint: Date and year (link)

[pmid20228059-5] Saini V, Marchese A, Majetschak M (May 2010). "CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin". J. Biol. Chem. 285 (20): 15566–76. doi:10.1074/jbc.M110.103408. PMC 2865327. PMID 20228059. CS1 maint: Date and year (link)

[pmid20689098-6] Majetschak M (August 2010). "Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules". J. Leukoc. Biol. 89 (2): 205–19. doi:10.1189/jlb.0510316. PMID 20689098. Check date values in: |year= / |date= mismatch (help)

[pmid17435771-7] Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR et al. (2007). "MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment". Nat. Med. 13 (5): 587–96. doi:10.1038/nm1567. PMID 17435771.

[pmid12183377-8] Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M et al. (September 2002). "The chemokine SDF1 regulates migration of dentate granule cells". Development 129 (18): 4249–60. PMID 12183377. CS1 maint: Date and year (link)

[pmid21832280-9] To LB, Levesque JP, Herbert KE (October 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. CS1 maint: Date and year (link)

[pmid18274673-10] Balabanian K, Levoye A, Klemm L, Lagane B, Hermine O, Harriague J et al. (March 2008). "Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling". J. Clin. Invest. 118 (3): 1074–84. doi:10.1172/JCI33187. PMC 2242619. PMID 18274673. CS1 maint: Date and year (link)

[pmid24366360-11] Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y et al. (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.

[pmid20839032-12] Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J et al. (December 2010). "CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression". Cancer Metastasis Rev. 29 (4): 709–22. doi:10.1007/s10555-010-9256-x. PMC 3175097. PMID 20839032. CS1 maint: Date and year (link)

[pmid15229479-13] Balkwill F (July 2004). "Cancer and the chemokine network". Nat. Rev. Cancer 4 (7): 540–50. doi:10.1038/nrc1388. PMID 15229479. CS1 maint: Date and year (link)

[pmid19646861-14] Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A et al. (September 2009). "CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival". Eur. J. Cancer 45 (14): 2579–87. doi:10.1016/j.ejca.2009.06.026. PMID 19646861. CS1 maint: Date and year (link)

[pmid21907922-15] Granot Z, Henke E, Comen EA, King TA, Norton L, Benezra R (September 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. CS1 maint: Date and year (link)

[16] LeCapitaine NJ, Zhang P, Winsauer P, Walker E, Vande Stouwe C, Porretta C et al. (2011). "Chronic Δ-9-tetrahydrocannabinol administration increases lymphocyte CXCR4 expression in rhesus macaques". J Neuroimmune Pharmacol 6 (4): 540–5. doi:10.1007/s11481-011-9277-4. PMC 3181271. PMID 21484257.

[pmid19106094-17] Mines MA, Goodwin JS, Limbird LE, Cui FF, Fan GH (February 2009). "Deubiquitination of CXCR4 by USP14 is critical for both CXCL12-induced CXCR4 degradation and chemotaxis but not ERK ativation". J. Biol. Chem. 284 (9): 5742–52. doi:10.1074/jbc.M808507200. PMC 2645827. PMID 19106094. CS1 maint: Date and year (link)

匿名

検索

案内

案内

CD184