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Gene Review

Cxcr4  -  chemokine (C-X-C motif) receptor 4

Mus musculus

Synonyms: C-X-C chemokine receptor type 4, CD184, CXC-R4, CXCR-4, Cmkar4, ...
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Disease relevance of Cxcr4


Psychiatry related information on Cxcr4


High impact information on Cxcr4

  • Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival [7].
  • These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1 [8].
  • SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion [8].
  • Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7 [9].
  • In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses [9].

Chemical compound and disease context of Cxcr4

  • The HIV-1 exterior envelope glycoprotein gp120 binds receptor (CD4) and co-receptors (CCR5/CXCR4) and is a major target for neutralizing antibodies [10].
  • The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry [11].
  • Systemic administration of the selective CXCR4 inhibitor AMD 3100 effectively blocked the enhanced metastatic potential of CXCR4-expressing pancreatic cancer cells [12].
  • Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells [13].
  • Inhibiting CXCR4 with RNAi, or the specific antagonist AMD3100, substantially delayed the growth of 4T1 cells in the lung, although neither RNAi nor AMD3100 prolonged overall survival in mice with experimental lung metastases [14].
  • The CXCR4 antagonist AMD3100 deteriorated the infarction and LV function after the MI in the M-CSF-treated mice [15].

Biological context of Cxcr4

  • This expression pattern suggests that Sdf1 and its receptor Cxcr4 may exert trophic influences on precursor cell proliferation and some neuronal targets that remain to be identified and studied further [16].
  • Changes in the distribution of the muscle progenitor cells were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but also control survival [17].
  • SDF-1 and its primary physiologic receptor CXCR4 have multiple essential functions in development including colonization of bone marrow by hematopoietic cells and neuron localization within cerebellum during embryogenesis as well as B lymphopoiesis and cardiovasculogenesis [18].
  • Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis [19].
  • However, only the death of sensory neurons seems to be a direct consequence of receptor inactivation as suggested by the observations that DRG neurons, but not motoneurons, of wild-type animals express CXCR4 and respond to CXCL12 with an increase in cell survival [3].

Anatomical context of Cxcr4

  • Thus, the status of Cxcr4 signaling helps to determine the initial axonal trajectory of mammalian motor neurons [20].
  • In prostate tumors, interestingly, Cxcl12 was up-regulated in epithelial cells with a concomitant expression of Cxcr4 [21].
  • Cxcr4 expression is progressively downregulated postnatally, but remains significantly associated in the adult with Bergman glia in the cerebellum, the subgranular layer of the dentate gyrus, and the olfactory glomerular layer [16].
  • Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5 [22].
  • We also find that CXCR4 can contribute to T cell homing [23].

Associations of Cxcr4 with chemical compounds

  • The biased effect of AMD3465 correlated with greater CXCR4 ligand expression in the type-2 model [2].
  • Furthermore, FTY720 administration uncovers a requirement for CXCR4 ligands for LN homing, but not for thymic egress, and CCR5 for thymic egress, but not LN homing [24].
  • In addition, treatment by injection with mAbs to CXCR4, integrin alpha2beta1, or integrin alpha5beta1 effectively inhibited the growth of HOS-CXCR4 transfectant cells in vivo [25].
  • Blockade of the CXCR4 receptor in normal thymocytes by AMD3100 led to the retention of mature T cells in the thymus in vitro and in vivo [26].
  • Cell surface expression of fusin in these cells was confirmed by staining with a polyclonal anti-fusin Ab [27].
  • Notch signaling is essential for DCs to transit from a dendrite(low)MHC II(low) immature state into a dendrite(high)MHC II(high) mature state, during the lipopolysaccharide-induced DC maturation, most likely through the up-regulation of CXCR4 [28].

Physical interactions of Cxcr4

  • In summary, our findings unravel a previously unrecognized complex role of CXCL12/CXCR4 in the control of limb neuromuscular development [3].
  • Importantly, the amino-terminal domain of SDF-1alpha which is required for binding to, and activation of, CXCR4 remains exposed after binding to HS and is recognized by a neutralizing monoclonal antibody directed against the first residues of the chemokine [29].
  • In contrast to this inhibition, G protein-coupled receptors such as CXCR4 and agonists mediating Ca2+ flux (inositol trisphosphate receptor subtype 2) are induced by TbetaR, indicating enhancement of the Ca2+ storage/ release system and chemotactic responses [30].
  • Gfi-1 binds to DNA sequences upstream of the CXCR4 gene and represses CXCR4 expression in myeloid lineage cells [31].

Co-localisations of Cxcr4


Regulatory relationships of Cxcr4

  • Together, CXCL12 acts on arterial endothelial cells of SMA to up-regulate CXCR4 and mediate the connection between the larger artery and neighboring capillary plexus in an organ-specific manner [33].
  • Cells expressing CXCR4 frequently coexpressed CCR2 receptors [34].
  • These altered chemokine responses did not appear to be due to enhanced expression of CXCR4 or lack of chemokine receptor expression [35].
  • We have found that SDF-1alpha and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) gamma-nonobese diabetic mouse [36].
  • In view of these data, we suggest that the impaired G-CSF-induced neutrophil mobilization in the absence of GRK6 may be a result of enhanced CXCR4-mediated retention of PMN in the bone marrow [37].

Other interactions of Cxcr4

  • Our analysis reveals a role of SDF1/CXCR4 signaling in the development of migrating muscle progenitors and shows that a threshold number of progenitor cells is required to generate muscle of appropriate size [17].
  • We found that CXCR4 and Gab1 interact genetically [17].
  • Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized [23].
  • Expression of chemokine receptors by neural progenitors was further confirmed using CXCR4-EGFP BAC transgenic mice [34].
  • These results suggest that the CXCR4/SDF-1alpha system mediates active MMP-9 and MMP-2 secretion from Hca-F and Hca-P cells, which facilitates lymphogenous metastasis of those cells consequently [4].

Analytical, diagnostic and therapeutic context of Cxcr4


  1. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Nagasawa, T., Nakajima, T., Tachibana, K., Iizasa, H., Bleul, C.C., Yoshie, O., Matsushima, K., Yoshida, N., Springer, T.A., Kishimoto, T. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation. Hu, J.S., Freeman, C.M., Stolberg, V.R., Chiu, B.C., Bridger, G.J., Fricker, S.P., Lukacs, N.W., Chensue, S.W. Am. J. Pathol. (2006) [Pubmed]
  3. Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Odemis, V., Lamp, E., Pezeshki, G., Moepps, B., Schilling, K., Gierschik, P., Littman, D.R., Engele, J. Mol. Cell. Neurosci. (2005) [Pubmed]
  4. Functional expression of CXC chemokine recepter-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability. Chu, H., Zhou, H., Liu, Y., Liu, X., Hu, Y., Zhang, J. Int. J. Biochem. Cell Biol. (2007) [Pubmed]
  5. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Zou, Y.R., Kottmann, A.H., Kuroda, M., Taniuchi, I., Littman, D.R. Nature (1998) [Pubmed]
  6. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Feng, Y., Broder, C.C., Kennedy, P.E., Berger, E.A. Science (1996) [Pubmed]
  7. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Kaneider, N.C., Agarwal, A., Leger, A.J., Kuliopulos, A. Nat. Med. (2005) [Pubmed]
  8. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Ceradini, D.J., Kulkarni, A.R., Callaghan, M.J., Tepper, O.M., Bastidas, N., Kleinman, M.E., Capla, J.M., Galiano, R.D., Levine, J.P., Gurtner, G.C. Nat. Med. (2004) [Pubmed]
  9. Involvement of chemokine receptors in breast cancer metastasis. Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M.E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S.N., Barrera, J.L., Mohar, A., Verástegui, E., Zlotnik, A. Nature (2001) [Pubmed]
  10. Characterization of antibody responses to purified HIV-1 gp120 glycoproteins fused with the molecular adjuvant C3d. Koch, M., Frazier, J., Sodroski, J., Wyatt, R. Virology (2005) [Pubmed]
  11. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Bleul, C.C., Farzan, M., Choe, H., Parolin, C., Clark-Lewis, I., Sodroski, J., Springer, T.A. Nature (1996) [Pubmed]
  12. CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer. Saur, D., Seidler, B., Schneider, G., Algül, H., Beck, R., Senekowitsch-Schmidtke, R., Schwaiger, M., Schmid, R.M. Gastroenterology (2005) [Pubmed]
  13. Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. Burger, M., Glodek, A., Hartmann, T., Schmitt-Gräff, A., Silberstein, L.E., Fujii, N., Kipps, T.J., Burger, J.A. Oncogene (2003) [Pubmed]
  14. CXCR4 regulates growth of both primary and metastatic breast cancer. Smith, M.C., Luker, K.E., Garbow, J.R., Prior, J.L., Jackson, E., Piwnica-Worms, D., Luker, G.D. Cancer Res. (2004) [Pubmed]
  15. Bone marrow-derived CXCR4+ cells mobilized by macrophage colony-stimulating factor participate in the reduction of infarct area and improvement of cardiac remodeling after myocardial infarction in mice. Morimoto, H., Takahashi, M., Shiba, Y., Izawa, A., Ise, H., Hongo, M., Hatake, K., Motoyoshi, K., Ikeda, U. Am. J. Pathol. (2007) [Pubmed]
  16. Expression of the chemokine receptor Cxcr4 mRNA during mouse brain development. Tissir, F., Wang, C.E., Goffinet, A.M. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  17. CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Vasyutina, E., Stebler, J., Brand-Saberi, B., Schulz, S., Raz, E., Birchmeier, C. Genes Dev. (2005) [Pubmed]
  18. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Ara, T., Nakamura, Y., Egawa, T., Sugiyama, T., Abe, K., Kishimoto, T., Matsui, Y., Nagasawa, T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  19. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Suratt, B.T., Petty, J.M., Young, S.K., Malcolm, K.C., Lieber, J.G., Nick, J.A., Gonzalo, J.A., Henson, P.M., Worthen, G.S. Blood (2004) [Pubmed]
  20. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Lieberam, I., Agalliu, D., Nagasawa, T., Ericson, J., Jessell, T.M. Neuron (2005) [Pubmed]
  21. Expression signature of the mouse prostate. Berquin, I.M., Min, Y., Wu, R., Wu, H., Chen, Y.Q. J. Biol. Chem. (2005) [Pubmed]
  22. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Allen, C.D., Ansel, K.M., Low, C., Lesley, R., Tamamura, H., Fujii, N., Cyster, J.G. Nat. Immunol. (2004) [Pubmed]
  23. Chemokine requirements for B cell entry to lymph nodes and Peyer's patches. Okada, T., Ngo, V.N., Ekland, E.H., Förster, R., Lipp, M., Littman, D.R., Cyster, J.G. J. Exp. Med. (2002) [Pubmed]
  24. FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. Yopp, A.C., Fu, S., Honig, S.M., Randolph, G.J., Ding, Y., Krieger, N.R., Bromberg, J.S. J. Immunol. (2004) [Pubmed]
  25. Chemokine receptor CXCR4-beta1 integrin axis mediates tumorigenesis of osteosarcoma HOS cells. Miura, K., Uniyal, S., Leabu, M., Oravecz, T., Chakrabarti, S., Morris, V.L., Chan, B.M. Biochem. Cell Biol. (2005) [Pubmed]
  26. A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cells from the fetal thymus. Vianello, F., Kraft, P., Mok, Y.T., Hart, W.K., White, N., Poznansky, M.C. J. Immunol. (2005) [Pubmed]
  27. Functional expression of the CXC-chemokine receptor-4/fusin on mouse microglial cells and astrocytes. Tanabe, S., Heesen, M., Yoshizawa, I., Berman, M.A., Luo, Y., Bleul, C.C., Springer, T.A., Okuda, K., Gerard, N., Dorf, M.E. J. Immunol. (1997) [Pubmed]
  28. Lipopolysaccharide-induced maturation of bone marrow-derived dendritic cells is regulated by notch signaling through the up-regulation of CXCR4. Wang, Y.C., Hu, X.B., He, F., Feng, F., Wang, L., Li, W., Zhang, P., Li, D., Jia, Z.S., Liang, Y.M., Han, H. J. Biol. Chem. (2009) [Pubmed]
  29. Stromal cell-derived factor-1alpha associates with heparan sulfates through the first beta-strand of the chemokine. Amara, A., Lorthioir, O., Valenzuela, A., Magerus, A., Thelen, M., Montes, M., Virelizier, J.L., Delepierre, M., Baleux, F., Lortat-Jacob, H., Arenzana-Seisdedos, F. J. Biol. Chem. (1999) [Pubmed]
  30. Redirection of B cell responsiveness by transforming growth factor beta receptor. Roes, J., Choi, B.K., Cazac, B.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  31. Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells. De La Luz Sierra, M., Gasperini, P., McCormick, P.J., Zhu, J., Tosato, G. Blood (2007) [Pubmed]
  32. Constitutive association of cell surface CCR5 and CXCR4 in the presence of CD4. Wang, J., Alvarez, R., Roderiquez, G., Guan, E., Norcross, M.A. J. Cell. Biochem. (2004) [Pubmed]
  33. The role of CXCL12 in the organ-specific process of artery formation. Ara, T., Tokoyoda, K., Okamoto, R., Koni, P.A., Nagasawa, T. Blood (2005) [Pubmed]
  34. Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. Tran, P.B., Banisadr, G., Ren, D., Chenn, A., Miller, R.J. J. Comp. Neurol. (2007) [Pubmed]
  35. Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses. Kim, C.H., Qu, C.K., Hangoc, G., Cooper, S., Anzai, N., Feng, G.S., Broxmeyer, H.E. J. Exp. Med. (1999) [Pubmed]
  36. The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas. Kayali, A.G., Van Gunst, K., Campbell, I.L., Stotland, A., Kritzik, M., Liu, G., Flodström-Tullberg, M., Zhang, Y.Q., Sarvetnick, N. J. Cell Biol. (2003) [Pubmed]
  37. GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. Vroon, A., Heijnen, C.J., Raatgever, R., Touw, I.P., Ploemacher, R.E., Premont, R.T., Kavelaars, A. J. Leukoc. Biol. (2004) [Pubmed]
  38. Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4. McGrath, K.E., Koniski, A.D., Maltby, K.M., McGann, J.K., Palis, J. Dev. Biol. (1999) [Pubmed]
  39. Syngenic bone marrow cells restore hepatic function in carbon tetrachloride-induced mouse liver injury. Jung, Y.J., Ryu, K.H., Cho, S.J., Woo, S.Y., Seoh, J.Y., Chun, C.H., Yoo, K., Moon, I.H., Han, H.S. Stem Cells Dev. (2006) [Pubmed]
  40. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Tögel, F., Isaac, J., Hu, Z., Weiss, K., Westenfelder, C. Kidney Int. (2005) [Pubmed]
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