Abstract
The G-CSF receptor (G-CSFR), like other members of the type-I cytokine receptor family, is a single transmembrane-spanning protein lacking intrinsic kinase activity, and is composed of an extracellular cytokine receptor homologous (CRH) domain containing four conserved cysteine residues and a Trp-Ser-X-Trp-Ser (WSXWS, where X is a nonconserved amino acid) motif, and shared elements in the intracellular region denoted as Box 1 and Box 2 (Fig. 1). This receptor also comprises an immunoglobulin (Ig)-like domain and 3 fibronectin type III (FNIII)-like domains in the extracellular portion, as well as a cytoplasmic region containing a conserved sequence termed Box 3 [1, 2].
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Larsen A, Davis T, Curtis BM et al (1990) Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains. J Exp Med 172:1559–1570
Fukunaga R, Ishizaka-Ikeda E, Seto Y, Nagata S (1990) Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell 61:341–350
Yamasaki K, Naito S, Anaguchi H, Ohkubo T, Ota Y (1997) Solution structure of an extracellular domain containing the WSxWS motif of the granulocyte colony-stimulating factor receptor and its interaction with ligand. Nat Struct Biol 4:498–504
Fukunaga R, Ishizaka-Ikeda E, Pan CX, Seto Y, Nagata S (1991) Functional domains of the granulocyte colony-stimulating factor receptor. EMBO J 10:2855–2865
Nicola NA, Peterson L (1986) Identification of distinct receptors for two hemopoietic growth factors (granulocyte colony-stimulating factor and multipotential colony-stimulating factor) by chemical cross-linking. J Biol Chem 261:12384–12389
Tamada T, Honjo E, Maeda Y et al (2006) Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex. Proc Natl Acad Sci U S A 103:3135–3140
McKinstry WJ, Li CL, Rasko JE, Nicola NA, Johnson GR, Metcalf D (1997) Cytokine receptor expression on hematopoietic stem and progenitor cells. Blood 89:65–71
Nicola NA, Metcalf D (1985) Binding of 125I-labeled granulocyte colony-stimulating factor to normal murine hemopoietic cells. J Cell Physiol 124:313–321
Manz MG, Miyamoto T, Akashi K, Weissman IL (2002) Prospective isolation of human clonogenic common myeloid progenitors. Proc Natl Acad Sci U S A 99:11872–11877
Liu F, Wu HY, Wesselschmidt R, Kornaga T, Link DC (1996) Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 5:491–501
Lieschke GJ, Grail D, Hodgson G et al (1994) Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84:1737–1746
Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T (2000) Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood 95:270–276
Morikawa K, Morikawa S, Nakamura M, Miyawaki T (2002) Characterization of granulocyte colony-stimulating factor receptor expressed on human lymphocytes. Br J Haematol 118:296–304
Shimoda K, Okamura S, Harada N, Kondo S, Okamura T, Niho Y (1993) Identification of a functional receptor for granulocyte colony-stimulating factor on platelets. J Clin Invest 91:1310–1313
Semerad CL, Christopher MJ, Liu F et al (2005) G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106:3020–3027
Liu F, Poursine-Laurent J, Link DC (2000) Expression of the G-CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G-CSF. Blood 95:3025–3031
Budel LM, Touw IP, Delwel R, Lowenberg B (1989) Granulocyte colony-stimulating factor receptors in human acute myelocytic leukemia. Blood 74:2668–2673
Corcione A, Corrias MV, Daniele S, Zupo S, Spriano M, Pistoia V (1996) Expression of granulocyte colony-stimulating factor and granulocyte colony-stimulating factor receptor genes in partially overlapping monoclonal B-cell populations from chronic lymphocytic leukemia patients. Blood 87:2861–2869
Trumpp A, Essers M, Wilson A (2010) Awakening dormant haematopoietic stem cells. Nat Rev Immunol 10:201–209
Calhoun DA, Donnelly WH Jr, Du Y, Dame JB, Li Y, Christensen RD (1999) Distribution of granulocyte colony-stimulating factor (G-CSF) and G-CSF-receptor mRNA and protein in the human fetus. Pediatr Res 46:333–338
Fukunaga R, Seto Y, Mizushima S, Nagata S (1990) Three different mRNAs encoding human granulocyte colony-stimulating factor receptor. Proc Natl Acad Sci U S A 87:8702–8706
Schneider A, Kruger C, Steigleder T et al (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115:2083–2098
Harada M, Qin Y, Takano H et al (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311
Bussolino F, Wang JM, Defilippi P et al (1989) Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 337:471–473
Seto Y, Fukunaga R, Nagata S (1992) Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor. J Immunol 148:259–266
Smith LT, Hohaus S, Gonzalez DA, Dziennis SE, Tenen DG (1996) PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood 88:1234–1247
Anderson KL, Smith KA, Conners K, McKercher SR, Maki RA, Torbett BE (1988) Myeloid development is selectively disrupted in PU.1 null mice. Blood 91:3702–3710
Aritomi M, Kunishima N, Okamoto T, Kuroki R, Ota Y, Morikawa K (1999) Atomic structure of the GCSF-receptor complex showing a new cytokine-receptor recognition scheme. Nature 401:713–717
Nicholson SE, Oates AC, Harpur AG, Ziemiecki A, Wilks AF, Layton JE (1994) Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation. Proc Natl Acad Sci U S A 91:2985–2988
Tian SS, Lamb P, Seidel HM, Stein RB, Rosen J (1994) Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Blood 84:1760–1764
Shimoda K, Feng J, Murakami H et al (1997) Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor. Blood 90:597–604
Rodig SJ, Meraz MA, White JM et al (1998) Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93:373–383
Parganas E, Wang D, Stravopodis D et al (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385–395
Dong F, van Buitenen C, Pouwels K, Hoefsloot LH, Lowenberg B, Touw IP (1993) Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation. Mol Cell Biol 13:7774–7781
Ziegler SF, Bird TA, Morella KK, Mosley B, Gearing DP, Baumann H (1993) Distinct regions of the human granulocyte-colony-stimulating factor receptor cytoplasmic domain are required for proliferation and gene induction. Mol Cell Biol 13:2384–2390
Fukunaga R, Ishizaka-Ikeda E, Nagata S (1993) Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony-stimulating factor receptor. Cell 74:1079–1087
Nicholson SE, Novak U, Ziegler SF, Layton JE (1995) Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. Blood 86:3698–3704
Tanner JW, Chen W, Young RL, Longmore GD, Shaw AS (1995) The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. J Biol Chem 270:6523–6530
Yoshikawa A, Murakami H, Nagata S (1995) Distinct signal transduction through the tyrosine-containing domains of the granulocyte colony-stimulating factor receptor. EMBO J 14:5288–5296
Akbarzadeh S, Ward AC, McPhee DO, Alexander WS, Lieschke GJ, Layton JE (2002) Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells. Blood 99:879–887
Aaronson DS, Horvath CM (2002) A road map for those who don’t know JAK-STAT. Science 296:1653–1655
Tian SS, Tapley P, Sincich C, Stein RB, Rosen J, Lamb P (1996) Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. Blood 88:4435–4444
Chakraborty A, Dyer KF, Cascio M, Mietzner TA, Tweardy DJ (1999) Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor. Blood 93:15–24
Ward AC, Hermans MH, Smith L et al (1999) Tyrosine-dependent and -independent mechanisms of STAT3 activation by the human granulocyte colony-stimulating factor (G-CSF) receptor are differentially utilized depending on G-CSF concentration. Blood 93:113–124
Shimozaki K, Nakajima K, Hirano T, Nagata S (1997) Involvement of STAT3 in the granulocyte colony-stimulating factor-induced differentiation of myeloid cells. J Biol Chem 272:25184–25189
Panopoulos AD, Bartos D, Zhang L, Watowich SS (2002) Control of myeloid-specific integrin alpha Mbeta 2 (CD11b/CD18) expression by cytokines is regulated by Stat3-dependent activation of PU.1. J Biol Chem 277:19001–19007
McLemore ML, Grewal S, Liu F et al (2001) STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. Immunity 14:193–204
de Koning JP, Soede-Bobok AA, Schelen AM et al (1998) Proliferation signaling and activation of Shc, p21Ras, and Myc via tyrosine 764 of human granulocyte colony-stimulating factor receptor. Blood 91:1924–1933
de Koning JP, Schelen AM, Dong F et al (1996) Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood 87:132–140
Ward AC, Smith L, de Koning JP, van Aesch Y, Touw IP (1999) Multiple signals mediate proliferation, differentiation, and survival from the granulocyte colony-stimulating factor receptor in myeloid 32D cells. J Biol Chem 274:14956–14962
Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA (1993) Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363:45–51
Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ (1994) Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Proc Natl Acad Sci U S A 91:4683–4687
Ward AC, Monkhouse JL, Csar XF, Touw IP, Bello PA (1998) The Src-like tyrosine kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF) and docks to the activated G-CSF receptor. Biochem Biophys Res Commun 251:117–123
Dong F, Larner AC (2000) Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the Janus kinases. Blood 95:1656–1662
Mermel CH, McLemore ML, Liu F et al (2006) Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis. Blood 108:2562–2568
Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824
Hortner M, Nielsch U, Mayr LM, Johnston JA, Heinrich PC, Haan S (2002) Suppressor of cytokine signaling-3 is recruited to the activated granulocyte-colony stimulating factor receptor and modulates its signal transduction. J Immunol 169:1219–1227
Irandoust MI, Aarts LH, Roovers O, Gits J, Erkeland SJ, Touw IP (2007) Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor. EMBO J 26:1782–1793
Roberts AW, Robb L, Rakar S et al (2001) Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc Natl Acad Sci U S A 98:9324–9329
Croker BA, Metcalf D, Robb L et al (2004) SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity 20:153–165
Auernhammer CJ, Bousquet C, Melmed S (1999) Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proc Natl Acad Sci U S A 96:6964–6969
Lee CK, Raz R, Gimeno R et al (2002) STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17:63–72
Tapley P, Shevde NK, Schweitzer PA et al (1997) Increased G-CSF responsiveness of bone marrow cells from hematopoietic cell phosphatase deficient viable motheaten mice. Exp Hematol 25:122–131
Ward AC, Oomen SP, Smith L et al (2000) The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor. Leukemia 14:1284–1291
Dong F, Qiu Y, Yi T, Touw IP, Larner AC (2001) The carboxyl terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of Stat activation. J Immunol 167:6447–6452
Hunter MG, Avalos BR (1999) Deletion of a critical internalization domain in the G-CSFR in acute myelogenous leukemia preceded by severe congenital neutropenia. Blood 93:440–446
Richards MK, Liu F, Iwasaki H, Akashi K, Link DC (2003) Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway. Blood 102:3562–3568
Liu F, Poursine-Laurent J, Wu HY, Link DC (1997) Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 90:2583–2590
Betsuyaku T, Liu F, Senior RM et al (1999) A functional granulocyte colony-stimulating factor receptor is required for normal chemoattractant-induced neutrophil activation. J Clin Invest 103:825–832
Nguyen-Jackson H, Panopoulos AD, Zhang H, Li HS, Watowich SS (2010) STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction. Blood 115:3354–3363
Panopoulos AD, Zhang L, Snow JW et al (2006) STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils. Blood 108:3682–3690
Germeshausen M, Skokowa J, Ballmaier M, Zeidler C, Welte K (2008) G-CSF receptor mutations in patients with congenital neutropenia. Curr Opin Hematol 15:332–337
von Vietinghoff S, Ley K (2008) Homeostatic regulation of blood neutrophil counts. J Immunol 181:5183–5188
Rosenberg PS, Alter BP, Bolyard AA et al (2006) The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107:4628–4635
Skokowa J, Cario G, Uenalan M et al (2006) LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med 12:1191–1197
Klein C, Grudzien M, Appaswamy G et al (2007) HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 39:86–92
Dale DC, Person RE, Bolyard AA et al (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96:2317–2322
Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP (1995) Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med 333:487–493
Dong F, Dale DC, Bonilla MA et al (1997) Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Leukemia 11:120–125
Germeshausen M, Ballmaier M, Welte K (2007) Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood 109:93–99
McLemore ML, Poursine-Laurent J, Link DC (1998) 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. J Clin Invest 102:483–492
Hermans MH, Antonissen C, Ward AC, Mayen AE, Ploemacher RE, Touw IP (1999) 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. J Exp Med 189:683–692
Liu F, Kunter G, Krem MM et al (2008) Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5. J Clin Invest 118:946–955
Kimura A, Rieger MA, Simone JM et al (2009) The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis. Blood 114:4721–4728
Bunting KD (2007) STAT5 signaling in normal and pathologic hematopoiesis. Front Biosci 12:2807–2820
Silver RT, Tefferi A (eds) (2008) Myeloproliferative disorders: biology and management. Informa Healthcare USA, Inc., New York
Plo I, Zhang Y, Le Couedic JP et al (2009) An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med 206:1701–1707
Forbes LV, Gale RE, Pizzey A, Pouwels K, Nathwani A, Linch DC (2002) An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. Oncogene 21:5981–5989
Takeda K, Noguchi K, Shi W et al (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 94:3801–3804
Durbin JE, Hackenmiller R, Simon MC, Levy DE (1996) Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84:443–450
Meraz MA, White JM, Sheehan KC et al (1996) Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431–442
Kamezaki K, Shimoda K, Numata A et al (2005) Roles of Stat3 and ERK in G-CSF signaling. Stem Cells 23:252–263
Welte T, Zhang SS, Wang T et al (2003) STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A 100:1879–1884
Cheers C, Haigh AM, Kelso A, Metcalf D, Stanley ER, Young AM (1988) Production of colony-stimulating factors (CSFs) during infection: separate determinations of macrophage-, granulocyte-, granulocyte-macrophage-, and multi-CSFs. Infect Immun 56:247–251
Lord BI, Molineux G, Pojda Z, Souza LM, Mermod JJ, Dexter TM (1991) Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo. Blood 77:2154–2159
Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS (2010) STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116:2462–2471
Hirai H, Zhang P, Dayaram T et al (2006) C/EBPbeta is required for ‘emergency’ granulopoiesis. Nat Immunol 7:732–739
Paslin D, Norman ME (1977) Atopic dermatitis and impaired neutrophil chemotaxis in Job’s syndrome. Arch Dermatol 113:801–805
Holland SM, DeLeo FR, Elloumi HZ et al (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619
Mintz R, Garty BZ, Meshel T et al (2010) Reduced expression of chemoattractant receptors by polymorphonuclear leukocytes in Hyper IgE Syndrome patients. Immunol Lett 130:97–106
Acknowledgments
HN-J is supported by an NIH predoctoral training grant in Cancer Immunology (T32-CA-09598-21). Related research in SSW’s laboratory has been supported by grants from the NIH (AI073587, AR059010), a Preclinical Research Agreement with Amgen Inc., and a seed grant from the Center for Stem Cell and Developmental Biology at UT M D Anderson Cancer Center.
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Nguyen-Jackson, H.T., Zhang, H., Watowich, S.S. (2012). G-CSF Receptor Structure, Function, and Intracellular Signal Transduction. In: Molineux, G., Foote, M., Arvedson, T. (eds) Twenty Years of G-CSF. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0348-0218-5_6
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