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CXCR4  -  chemokine (C-X-C motif) receptor 4

Homo sapiens

Synonyms: C-X-C chemokine receptor type 4, CD184, CXC-R4, CXCR-4, D2S201E, ...
 
 
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Disease relevance of CXCR4

  • CXCR4, another important HIV-1 coreceptor, is also sulfated [1].
  • In the present report, we show that one member of this family, termed Fusin/ CXCR4, is able to function as an alternative receptor for some isolates of HIV-2 in the absence of CD4 [2].
  • Deletion of the COOH-terminal, cytoplasmic domain of CXCR4 did not affect HIV entry, but prevented SDF-1alpha-induced receptor downregulation and decreased the potency of SDF-1alpha as inhibitor of HIV replication [3].
  • Signaling from both CCR5 and CXCR4 is mediated by pertussis toxin (PTX)-sensitive G(i) proteins and is not required for HIV-1 entry [4].
  • The Env from the parental virus as well as one derived from the first macaque to develop AIDS exclusively used CXCR4 as a coreceptor, indicating that CXCR4 can function as a coreceptor in macaques even though it is rarely used by simian immunodeficiency viruses [5].
  • Our data demonstrate the feasibility of imaging CXCR4 expression in experimental brain tumors [6].
 

Psychiatry related information on CXCR4

  • Although these chemokine receptors could be detected on Lin(-) cells throughout human development, only CXCR4 could be detected in CD34(-)CD38(-)Lin(-) and CD34(+)CD38(-)Lin(-) subfractions enriched for stem cell function, suggesting that independent of ontogeny, CXCR4-mediated signals are critical to primitive hematopoiesis [7].
  • The limbic system plays a key role in memory, and the presence of CXCR4-which can bind the viral envelope protein gp120-min a subset of neurons from this system may play a role in the development of HIV-related dementia [8].
  • Here we address whether CCR5 or CXCR4 tropism of the predominant viral strain detected before or on combination antiretroviral therapy (ART) explains why some human immunodeficiency virus (HIV)-infected patients who begin ART with advanced HIV disease retain low interferon (IFN)-gamma responses, despite recovery of CD4(+) T cell counts [9].
  • Our results show that LT-NPs manifest increased CTL activity and IL-16 expression and decreased expression of TGF-beta1 and CXCR4 compared to NPs, regardless of recreational drug usage [10].
  • RESULTS: All constructed cell lines expressing the various CXCR4 glycomutants showed similar permissiveness for the X4-monotropic virus and no change in the coreceptor specificity that allows infection of a CCR5-dependent R5-monotropic virus [11].
 

High impact information on CXCR4

  • Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor [12].
  • The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection [12].
  • A CXCR4/CD4 pseudotype rhabdovirus that selectively infects HIV-1 envelope protein-expressing cells [13].
  • We describe a recombinant vesicular stomatitis virus lacking its glycoprotein gene and expressing instead the HIV-1 receptor CD4 and a coreceptor, CXCR4 [14].
  • A dual-tropic primary HIV-1 isolate (89.6) utilizes both Fusin and CKR-5 as entry cofactors [15].
 

Chemical compound and disease context of CXCR4

 

Biological context of CXCR4

 

Anatomical context of CXCR4

 

Associations of CXCR4 with chemical compounds

  • In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell-derived factor 1alpha, the natural ligand for CXCR4 [27].
  • Removal of SDF-1alpha led to rapid, but incomplete surface reexpression of CXCR4, a process that was not inhibited by cycloheximide, suggesting that the coreceptor is recycling from the internalization pool [3].
  • During 1996, the necessary entry co-factors (co-receptors or second receptors) were identified as being members of the seven-transmembrane-spanning receptor family fusin: CXCR4 for T-tropic strains and CCR5, principally, for M-tropic strains [28].
  • In addition to CD4, different gp120 isolates bind to the alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively [23].
  • The PDTC-mediated inhibition of CCR5 and CXCR4 mRNA expression was associated with decreased chemotactic responsiveness (>90% inhibition) and with a marked inhibition of surface-receptor expression [29].
 

Physical interactions of CXCR4

 

Enzymatic interactions of CXCR4

  • Furthermore, within seconds of SDF-1alpha activation, the CXCR4 receptor becomes tyrosine phosphorylated through the activation and association with the receptor of JAK2 and JAK3 kinases [35].
  • Moreover, tyrosine-phosphorylated syndecan-4 from CXCL12-stimulated HeLa cells physically coassociates with tyrosine phosphorylated CXCR4 [36].
 

Co-localisations of CXCR4

  • SDF-1alpha and gp120 induce the appearance of pseudopodia in which CD26 and CXCR4 colocalize and in which ADA is not present [37].
 

Regulatory relationships of CXCR4

 

Other interactions of CXCR4

  • The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1 [38].
  • In children who progressed to AIDS without a shift to CXCR4 usage, all the sequential isolates were CCR5-dependent but showed a reduced sensitivity to C-C chemokines [26].
  • By contrast, the majority of the isolates derived after the progression of the disease were resistant to C-C chemokines, having acquired the ability to use CXCR4 and, in some cases, CCR3, while gradually losing CCR5 usage [26].
  • Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells [44].
  • There is also evidence for expression of chemokine receptors CCR4 and CXCR4 in platelets [45].
  • Taken together, these results have revealed a pivotal role for GRK3 in regulating CXCR4 attenuation and have provided a mechanistic link between the GRK3 pathway and the CXCR4-related WHIM(WT) disorder [46].
 

Analytical, diagnostic and therapeutic context of CXCR4

References

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  2. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Endres, M.J., Clapham, P.R., Marsh, M., Ahuja, M., Turner, J.D., McKnight, A., Thomas, J.F., Stoebenau-Haggarty, B., Choe, S., Vance, P.J., Wells, T.N., Power, C.A., Sutterwala, S.S., Doms, R.W., Landau, N.R., Hoxie, J.A. Cell (1996) [Pubmed]
  3. HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. Amara, A., Gall, S.L., Schwartz, O., Salamero, J., Montes, M., Loetscher, P., Baggiolini, M., Virelizier, J.L., Arenzana-Seisdedos, F. J. Exp. Med. (1997) [Pubmed]
  4. The B-oligomer of pertussis toxin deactivates CC chemokine receptor 5 and blocks entry of M-tropic HIV-1 strains. Alfano, M., Schmidtmayerova, H., Amella, C.A., Pushkarsky, T., Bukrinsky, M. J. Exp. Med. (1999) [Pubmed]
  5. HIV type I envelope determinants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Hoffman, T.L., Stephens, E.B., Narayan, O., Doms, R.W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
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  7. Characterization of chemokine receptors expressed in primitive blood cells during human hematopoietic ontogeny. Rosu-Myles, M., Khandaker, M., Wu, D.M., Keeney, M., Foley, S.R., Howson-Jan, K., Yee, I.C., Fellows, F., Kelvin, D., Bhatia, M. Stem Cells (2000) [Pubmed]
  8. Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. van der Meer, P., Ulrich, A.M., Gonźalez-Scarano, F., Lavi, E. Exp. Mol. Pathol. (2000) [Pubmed]
  9. Brief Report: CXCR4 or CCR5 Tropism of Human Immunodeficiency Virus Type 1 Isolates Does Not Determine the Immunological Milieu in Patients Responding to Antiretroviral Therapy. Price, P., Keane, N., Gray, L., Lee, S., Gorry, P.R., French, M.A. Viral Immunol. (2006) [Pubmed]
  10. Association of drug abuse with inhibition of HIV-1 immune responses: studies with long-term of HIV-1 non-progressors. Nair, M.P., Mahajan, S., Hewitt, R., Whitney, Z.R., Schwartz, S.A. J. Neuroimmunol. (2004) [Pubmed]
  11. Infection of cells expressing CXCR4 mutants lacking N-glycosylation at the N-terminal extracellular domain is enhanced for R5X4-dualtropic human immunodeficiency virus type-1. Thordsen, I., Polzer, S., Schreiber, M. BMC Infect. Dis. (2002) [Pubmed]
  12. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Hernandez, P.A., Gorlin, R.J., Lukens, J.N., Taniuchi, S., Bohinjec, J., Francois, F., Klotman, M.E., Diaz, G.A. Nat. Genet. (2003) [Pubmed]
  13. A CXCR4/CD4 pseudotype rhabdovirus that selectively infects HIV-1 envelope protein-expressing cells. Mebatsion, T., Finke, S., Weiland, F., Conzelmann, K.K. Cell (1997) [Pubmed]
  14. Construction of a novel virus that targets HIV-1-infected cells and controls HIV-1 infection. Schnell, M.J., Johnson, J.E., Buonocore, L., Rose, J.K. Cell (1997) [Pubmed]
  15. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Doranz, B.J., Rucker, J., Yi, Y., Smyth, R.J., Samson, M., Peiper, S.C., Parmentier, M., Collman, R.G., Doms, R.W. Cell (1996) [Pubmed]
  16. CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Hesselgesser, J., Halks-Miller, M., DelVecchio, V., Peiper, S.C., Hoxie, J., Kolson, D.L., Taub, D., Horuk, R. Curr. Biol. (1997) [Pubmed]
  17. Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. Robledo, M.M., Bartolome, R.A., Longo, N., Rodríguez-Frade, J.M., Mellado, M., Longo, I., van Muijen, G.N., Sánchez-Mateos, P., Teixidó, J. J. Biol. Chem. (2001) [Pubmed]
  18. Inhibition of CXCR4-tropic HIV-1 infection by lipopolysaccharide: evidence of different mechanisms in macrophages and T lymphocytes. Verani, A., Sironi, F., Siccardi, A.G., Lusso, P., Vercelli, D. J. Immunol. (2002) [Pubmed]
  19. Interleukin-8-mediated heterologous receptor internalization provides resistance to HIV-1 infectivity. Role of signal strength and receptor desensitization. Richardson, R.M., Tokunaga, K., Marjoram, R., Sata, T., Snyderman, R. J. Biol. Chem. (2003) [Pubmed]
  20. Human melanoma metastases express functional CXCR4. Scala, S., Giuliano, P., Ascierto, P.A., Ieranò, C., Franco, R., Napolitano, M., Ottaiano, A., Lombardi, M.L., Luongo, M., Simeone, E., Castiglia, D., Mauro, F., De Michele, I., Calemma, R., Botti, G., Caracò, C., Nicoletti, G., Satriano, R.A., Castello, G. Clin. Cancer Res. (2006) [Pubmed]
  21. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. Murakami, T., Nakajima, T., Koyanagi, Y., Tachibana, K., Fujii, N., Tamamura, H., Yoshida, N., Waki, M., Matsumoto, A., Yoshie, O., Kishimoto, T., Yamamoto, N., Nagasawa, T. J. Exp. Med. (1997) [Pubmed]
  22. Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. Jordan, N.J., Kolios, G., Abbot, S.E., Sinai, M.A., Thompson, D.A., Petraki, K., Westwick, J. J. Clin. Invest. (1999) [Pubmed]
  23. Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Kaul, M., Lipton, S.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  24. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Libura, J., Drukala, J., Majka, M., Tomescu, O., Navenot, J.M., Kucia, M., Marquez, L., Peiper, S.C., Barr, F.G., Janowska-Wieczorek, A., Ratajczak, M.Z. Blood (2002) [Pubmed]
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