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Gene Review

Csf3r  -  colony stimulating factor 3 receptor...

Mus musculus

Synonyms: Cd114, Csfgr, G-CSF receptor, G-CSF-R, G-CSFR, ...
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Disease relevance of Csf3r


High impact information on Csf3r


Biological context of Csf3r


Anatomical context of Csf3r

  • Surprisingly, G-CSFR expression on neutrophils is neither necessary nor sufficient for their mobilization from the bone marrow, suggesting that G-CSF induces neutrophil mobilization indirectly through the generation of trans-acting signals [11].
  • This defect was not due to a failure to regenerate HPC following cyclophosphamide administration as the number of CFU-C in the bone marrow of G-CSFR-deficient mice was increased relative to wild-type mice [12].
  • We generated mice with an equivalent mutation (gcsfr-triangle Delta715) by homologous and Cre-mediated recombination in embryonic stem cells [13].
  • To directly test whether G-CSF can compensate for the myeloid progenitor cell reduction in the T(-) model of hematopoietic deficiency, T(-) and G-CSF-receptor knock-out (GR(-)) mice were crossed, and F1 animals bred to obtain doubly nullizygous mice (T(-)GR(-)) [14].
  • Under steady-state conditions the G-CSF-R localized predominantly to the Golgi apparatus, late endosomes, and lysosomes, with only low expression on the plasma membrane, resulting from spontaneous internalization [7].

Associations of Csf3r with chemical compounds

  • We generated G-CSF-R-deficient mice and transduced their bone marrow cells with tyrosine "null" mutant (m0), single tyrosine "add-back" mutants, or wild-type (WT) receptors [8].
  • In contrast to wild-type mice, no increase in circulating colony-forming cells (CFU-C), CD34+ lineage- progenitors, or day 12 colony-forming unit-spleen progenitors (CFU-S) was detected in G-CSFR-deficient mice after cyclophosphamide administration [12].
  • It is interesting that activation of these signaling molecules by G-CSF was prolonged by pretreating cells with actinomycin D or cyclohexamide, suggesting that de novo protein synthesis is required for appropriate termination of G-CSF-R signaling [15].
  • The SAG is a chimeric gene encoding the G-CSF receptor (GCR) and the estrogen or tamoxifen (Tm) receptor and is able to expand transduced hematopoietic cells by treatment with estrogen or Tm [16].
  • We constructed mutant receptors in which each tyrosine residue of G-CSFR was mutated to phenylalanine [17].

Physical interactions of Csf3r

  • Granulocyte colony-stimulating factor (G-CSF) is the major regulator of granulopoiesis and acts through binding to its specific receptor (G-CSF-R) on neutrophilic granulocytes [18].
  • To this end, we constructed a chimeric cDNA (GCRER) encoding the fusion protein between the granulocyte colony-stimulating factor receptor (G-CSFR) and the hormone-binding domain (HBD) of the estrogen receptor (ER) as a selective amplifier gene [19].

Enzymatic interactions of Csf3r

  • Because a high concentration of G-CSF was observed in the supernatants of leukemic blast cells from these two cases, it seems likely that the soluble G-CSF receptor cut off the autocrine growth mechanism of leukemic blast cells mediated by G-CSF [20].

Regulatory relationships of Csf3r

  • The mouse myeloid leukemic cell line (M1) transfected with G-CSF-R cDNA can be induced to differentiate into macrophages in response to G-CSF [21].
  • The Mpl-type SAGs induced more potent proliferation of Ba/F3 and cynomolgus CD34(+) cells than the GCR-type SAG [16].
  • The ability of tyrosine-to-phenylalanine substitution mutants of the G-CSF receptor to activate STAT3 strongly correlated with their capacity to induce p27 expression and their ability to mediate differentiation and survival, suggesting a causal relationship between STAT3 activation, p27 expression and the observed cellular responses [22].
  • Mutation of the most distal tyrosine residue (Tyr763) abolished the ability of G-CSFR to stimulate the tyrosine phosphorylation of a cellular protein with an M(r) of 54 kDa [17].
  • G-CSF-induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r [23].

Other interactions of Csf3r

  • Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice [14].
  • These results indicated that receptors belonging to different receptor families can be functionally exchanged and confirm that a homodimer of G-CSFR can transduce the growth signal, whereas Fas must be oligomerized (probably trimerized) to transduce the apoptotic signal [24].
  • These results show that the G-CSFR is required for mobilization in response to cyclophosphamide or IL-8 but not flt-3 ligand and suggest that the G-CSFR may play an important and previously unexpected role in HPC migration [12].
  • In semi-solid medium assays, G-CSFR-infected cells gave rise to all types of colonies [granulocyte-macrophage (GM), megakaryocyte (MK) and mixed lineage (GEMM) colony-forming units (CFU) and erythroid burst-forming units (BFU-E)] in the presence of G-CSF alone [25].
  • The role of mutations of the granulocyte colony-stimulating factor receptor (G-CSFR) in the pathogenesis of severe congenital neutropenia (SCN) and the subsequent development of acute myeloid leukemia (AML) is controversial [26].

Analytical, diagnostic and therapeutic context of Csf3r


  1. Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. Hermans, M.H., Antonissen, C., Ward, A.C., Mayen, A.E., Ploemacher, R.E., Touw, I.P. J. Exp. Med. (1999) [Pubmed]
  2. Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice. Mitsui, T., Watanabe, S., Taniguchi, Y., Hanada, S., Ebihara, Y., Sato, T., Heike, T., Mitsuyama, M., Nakahata, T., Tsuji, K. Blood (2003) [Pubmed]
  3. Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol. Jordà, M.A., Verbakel, S.E., Valk, P.J., Vankan-Berkhoudt, Y.V., Maccarrone, M., Finazzi-Agrò, A., Löwenberg, B., Delwel, R. Blood (2002) [Pubmed]
  4. Molecular cloning of cDNAs for the human granulocyte colony-stimulating factor receptor from HL-60 and mapping of the gene to chromosome region 1p32-34. Tweardy, D.J., Anderson, K., Cannizzaro, L.A., Steinman, R.A., Croce, C.M., Huebner, K. Blood (1992) [Pubmed]
  5. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Fukunaga, R., Ishizaka-Ikeda, E., Seto, Y., Nagata, S. Cell (1990) [Pubmed]
  6. STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. McLemore, M.L., Grewal, S., Liu, F., Archambault, A., Poursine-Laurent, J., Haug, J., Link, D.C. Immunity (2001) [Pubmed]
  7. Receptor activation and 2 distinct COOH-terminal motifs control G-CSF receptor distribution and internalization kinetics. Aarts, L.H., Roovers, O., Ward, A.C., Touw, I.P. Blood (2004) [Pubmed]
  8. Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Hermans, M.H., van de Geijn, G.J., Antonissen, C., Gits, J., van Leeuwen, D., Ward, A.C., Touw, I.P. Blood (2003) [Pubmed]
  9. Regulation of LIP level and ROS formation through interaction of H-ferritin with G-CSF receptor. Yuan, X., Cong, Y., Hao, J., Shan, Y., Zhao, Z., Wang, S., Chen, J. J. Mol. Biol. (2004) [Pubmed]
  10. Dissociation of the Jak kinase pathway from G-CSF receptor signaling in neutrophils. Avalos, B.R., Parker, J.M., Ware, D.A., Hunter, M.G., Sibert, K.A., Druker, B.J. Exp. Hematol. (1997) [Pubmed]
  11. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Semerad, C.L., Liu, F., Gregory, A.D., Stumpf, K., Link, D.C. Immunity (2002) [Pubmed]
  12. The granulocyte colony-stimulating factor receptor is required for the mobilization of murine hematopoietic progenitors into peripheral blood by cyclophosphamide or interleukin-8 but not flt-3 ligand. Liu, F., Poursine-Laurent, J., Link, D.C. Blood (1997) [Pubmed]
  13. Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Hermans, M.H., Ward, A.C., Antonissen, C., Karis, A., Löwenberg, B., Touw, I.P. Blood (1998) [Pubmed]
  14. Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice. Kaushansky, K., Fox, N., Lin, N.L., Liles, W.C. Blood (2002) [Pubmed]
  15. Tyrosine 729 of the G-CSF receptor controls the duration of receptor signaling: involvement of SOCS3 and SOCS1. Zhuang, D., Qiu, Y., Haque, S.J., Dong, F. J. Leukoc. Biol. (2005) [Pubmed]
  16. New selective amplifier genes containing c-Mpl for hematopoietic cell expansion. Nagashima, T., Ueda, Y., Hanazono, Y., Kume, A., Shibata, H., Ageyama, N., Terao, K., Ozawa, K., Hasegawa, M. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  17. Distinct signal transduction through the tyrosine-containing domains of the granulocyte colony-stimulating factor receptor. Yoshikawa, A., Murakami, H., Nagata, S. EMBO J. (1995) [Pubmed]
  18. Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells. Akbarzadeh, S., Ward, A.C., McPhee, D.O., Alexander, W.S., Lieschke, G.J., Layton, J.E. Blood (2002) [Pubmed]
  19. Development of a novel selective amplifier gene for controllable expansion of transduced hematopoietic cells. Ito, K., Ueda, Y., Kokubun, M., Urabe, M., Inaba, T., Mano, H., Hamada, H., Kitamura, T., Mizoguchi, H., Sakata, T., Hasegawa, M., Ozawa, K. Blood (1997) [Pubmed]
  20. Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells from patients with acute myeloblastic leukemia. Asano, Y., Yokoyama, T., Shibata, S., Kobayashi, S., Shimoda, K., Nakashima, H., Okamura, S., Niho, Y. Cancer Res. (1997) [Pubmed]
  21. Tyrosine residues in the granulocyte colony-stimulating factor (G-CSF) receptor mediate G-CSF-induced differentiation of murine myeloid leukemic (M1) cells. Nicholson, S.E., Starr, R., Novak, U., Hilton, D.J., Layton, J.E. J. Biol. Chem. (1996) [Pubmed]
  22. STAT3-mediated differentiation and survival and of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27(Kip1). de Koning, J.P., Soede-Bobok, A.A., Ward, A.C., Schelen, A.M., Antonissen, C., van Leeuwen, D., Löwenberg, B., Touw, I.P. Oncogene (2000) [Pubmed]
  23. Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5. Liu, F., Kunter, G., Krem, M.M., Eades, W.C., Cain, J.A., Tomasson, M.H., Hennighausen, L., Link, D.C. J. Clin. Invest. (2008) [Pubmed]
  24. Swapping between Fas and granulocyte colony-stimulating factor receptor. Takahashi, T., Tanaka, M., Ogasawara, J., Suda, T., Murakami, H., Nagata, S. J. Biol. Chem. (1996) [Pubmed]
  25. The granulocyte colony-stimulating factor receptor supports erythroid differentiation in the absence of the erythropoietin receptor or Stat5. Millot, G.A., Svinarchuk, F., Lacout, C., Vainchenker, W., Dumenil, D. Br. J. Haematol. (2001) [Pubmed]
  26. Increased granulocyte colony-stimulating factor responsiveness but normal resting granulopoiesis in mice carrying a targeted granulocyte colony-stimulating factor receptor mutation derived from a patient with severe congenital neutropenia. McLemore, M.L., Poursine-Laurent, J., Link, D.C. J. Clin. Invest. (1998) [Pubmed]
  27. Regulation of the differentiation of WEHI-3B D+ leukemia cells by granulocyte colony-stimulating factor receptor. Li, J., Koay, D.C., Xiao, H., Sartorelli, A.C. J. Cell Biol. (1993) [Pubmed]
  28. "Emergency" granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. Basu, S., Hodgson, G., Zhang, H.H., Katz, M., Quilici, C., Dunn, A.R. Blood (2000) [Pubmed]
  29. Circular permutation of the granulocyte colony-stimulating factor receptor agonist domain of myelopoietin. McWherter, C.A., Feng, Y., Zurfluh, L.L., Klein, B.K., Baganoff, M.P., Polazzi, J.O., Hood, W.F., Paik, K., Abegg, A.L., Grabbe, E.S., Shieh, J.J., Donnelly, A.M., McKearn, J.P. Biochemistry (1999) [Pubmed]
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