|Chemokine (C-X-C motif) receptor 4|
CXCR4 in complex with IT1t(PDB )
|Symbols||; CD184; D2S201E; FB22; HM89; HSY3RR; LAP-3; LAP3; LCR1; LESTR; NPY3R; NPYR; NPYRL; NPYY3R; WHIM|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
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; 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. 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. 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. It is speculated this interaction may be through CXCR4 mediated signalling pathways. MIF is an additional ligand of CXCR4
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.
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, which directly blocks the CXCR4 receptor. It is a very efficient inducer of hematopoietic stem cell mobilization in animal and human studies.
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. 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. 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.
- Moriuchi M, Moriuchi H, Turner W, Fauci A (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.
- Caruz A, Samsom M, Alonso J, Alcami J, Baleux F, Virelizier J 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.
- Tamamis P, Floudas C (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.
- Tamamis P, Floudas C (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.
- 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.
- 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.
- Bernhagen J, Krohn R, Lue H, Gregory J, Zernecke A, Koenen R 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 Y, Littman D, Tessier-Lavigne M et al. (September 2002). "The chemokine SDF1 regulates migration of dentate granule cells". Development 129 (18): 4249–60. PMID 12183377.
- To L, Levesque J, Herbert K (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.
- 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.
- Hunter Z, 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.
- Balkwill F (July 2004). "Cancer and the chemokine network". Nat. Rev. Cancer 4 (7): 540–50. doi:10.1038/nrc1388. PMID 15229479.
- Mirisola V, Zuccarino A, Bachmeier B, Sormani M, 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.
- Granot Z, Henke E, Comen E, King T, 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.
- LeCapitaine N, 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 M, Goodwin J, Limbird L, Cui F, Fan G (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.
- Wilkinson D (1996). "Cofactors provide the entry keys. HIV-1". Curr. Biol. 6 (9): 1051–3. doi:10.1016/S0960-9822(02)70661-1. PMID 8805353.
- Broder C, Dimitrov D (1996). "HIV and the 7-transmembrane domain receptors". Pathobiology 64 (4): 171–9. doi:10.1159/000164032. PMID 9031325.
- Choe H, Martin K, Farzan M, Sodroski J, Gerard N, Gerard C (1998). "Structural interactions between chemokine receptors, gp120 Env and CD4". Semin. Immunol. 10 (3): 249–57. doi:10.1006/smim.1998.0127. PMID 9653051.
- Freedman B, Liu Q, Del Corno M, Collman R (2003). "HIV-1 gp120 chemokine receptor-mediated signaling in human macrophages". Immunol. Res. 27 (2-3): 261–76. doi:10.1385/IR:27:2-3:261. PMID 12857973.
- Esté J (2003). "Virus entry as a target for anti-HIV intervention". Curr. Med. Chem. 10 (17): 1617–32. doi:10.2174/0929867033457098. PMID 12871111.
- Gallo S, Finnegan C, Viard M, Raviv Y, Dimitrov A, Rawat S et al. (2003). "The HIV Env-mediated fusion reaction". Biochim. Biophys. Acta 1614 (1): 36–50. doi:10.1016/S0005-2736(03)00161-5. PMID 12873764.
- Zaitseva M, Peden K, Golding H (2003). "HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral-cell fusion and as targets for entry inhibitors". Biochim. Biophys. Acta 1614 (1): 51–61. doi:10.1016/S0005-2736(03)00162-7. PMID 12873765.
- Lee C, Liu Q, Tomkowicz B, Yi Y, Freedman B, Collman R (2003). "Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways". J. Leukoc. Biol. 74 (5): 676–82. doi:10.1189/jlb.0503206. PMID 12960231.
- Yi Y, Lee C, Liu Q, Freedman B, Collman R (2004). "Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis". J. Neurovirol. 10. 10 Suppl 1: 91–6. doi:10.1080/753312758. PMID 14982745.
- Seibert C, Sakmar T (2004). "Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs". Curr. Pharm. Des. 10 (17): 2041–62. doi:10.2174/1381612043384312. PMID 15279544.
- Perfettini J, Castedo M, Roumier T, Andreau K, Nardacci R, Piacentini M et al. (2005). "Mechanisms of apoptosis induction by the HIV-1 envelope". Cell Death Differ. 12. 12 Suppl 1: 916–23. doi:10.1038/sj.cdd.4401584. PMID 15719026.
- King J, Eugenin E, Buckner C, Berman J (2006). "HIV tat and neurotoxicity". Microbes Infect. 8 (5): 1347–57. doi:10.1016/j.micinf.2005.11.014. PMID 16697675.
- Kryczek I, Wei S, Keller E, Liu R, Zou W (2007). "Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis". Am. J. Physiol., Cell Physiol. 292 (3): C987–95. doi:10.1152/ajpcell.00406.2006. PMID 16943240.
- Arya M, Ahmed H, Silhi N, Williamson M, Patel H (2007). "Clinical importance and therapeutic implications of the pivotal CXCL12-CXCR4 (chemokine ligand-receptor) interaction in cancer cell migration". Tumour Biol. 28 (3): 123–31. doi:10.1159/000102979. PMID 17510563.
- Grange J (1979). "Tuberculosis: the changing tubercle". Br J Hosp Med 22 (6): 540–8. PMID 118789.
- Nomura H, Nielsen B, Matsushima K (1993). "Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors". Int. Immunol. 5 (10): 1239–49. doi:10.1093/intimm/5.10.1239. PMID 7505609.
- Lu Z, Wang Z, Horuk R, Hesselgesser J, Lou Y, Hadley T et al. (1995). "The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain". J. Biol. Chem. 270 (44): 26239–45. doi:10.1074/jbc.270.44.26239. PMID 7592830.
- Jazin E, Yoo H, Blomqvist A, Yee F, Weng G, Walker M et al. (1993). "A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells". Regul. Pept. 47 (3): 247–58. doi:10.1016/0167-0115(93)90392-L. PMID 8234909.
- Loetscher M, Geiser T, O'Reilly T, Zwahlen R, Baggiolini M, Moser B (1994). "Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes". J. Biol. Chem. 269 (1): 232–7. PMID 8276799.
- Federsppiel B, Melhado I, Duncan A, Delaney A, Schappert K, Clark-Lewis I et al. (1993). "Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen". Genomics 16 (3): 707–12. doi:10.1006/geno.1993.1251. PMID 8325644.
- "Chemokine Receptors: CXCR4". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.