Granulocyte colony-stimulating factor receptor explained

The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 (Cluster of Differentiation 114) is a protein that in humans is encoded by the CSF3R gene.^[1] G-CSF-R is a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF).^[2] The G-CSF receptors belong to a family of cytokine receptors known as the hematopoietin receptor family. The granulocyte colony-stimulating factor receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.

The G-CSF-R is a transmembrane receptor that consists of an extracellular ligand-binding portion, a transmembrane domain, and the cytoplasmic portion that is responsible for signal transduction. GCSF-R ligand-binding is associated with dimerization of the receptor and signal transduction through proteins including Jak, Lyn, STAT, and Erk1/2.

Isoforms

The class IV isoform defective for both internalization and differentiation signaling,^[3] and colony-stimulating.

Clinical significance

Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia.^[4]

Mutations in the intracellular part of this receptor are also associated with certain types of leukemia.^[5]

In clinical medicine, there is a suggestion that use of GCSF should be avoided, at least in children and adolescents and perhaps adults, when G-CSFR isoform IV is overexpressed.^[6]

Interactions

Granulocyte colony-stimulating factor receptor has been shown to interact with Grb2,^[7] HCK^[8] and SHC1.^[7]

See also

• Cluster of differentiation

Further reading

• Tsuji K, Ebihara Y . Expression of G-CSF receptor on myeloid progenitors. . Leuk. Lymphoma . 42 . 6 . 1351–7 . 2002 . 11911419 . 10.3109/10428190109097763 . 8010177 .
• Kimura A, Sultana TA . Granulocyte colony-stimulating factor receptors on CD34++ cells in patients with myelodysplastic syndrome (MDS) and MDS-acute myeloid leukemia. . Leuk. Lymphoma . 45 . 10 . 1995–2000 . 2005 . 15370243 . 10.1080/10428190410001714034 . 36625508 .
• Tweardy DJ, Anderson K, Cannizzaro LA, Steinman RA, Croce CM, Huebner K . 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. . Blood . 79 . 5 . 1148–54 . 1992 . 10.1182/blood.V79.5.1148.1148 . 1371413 . free .
• Seto Y, Fukunaga R, Nagata S . Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor. . J. Immunol. . 148 . 1 . 259–66 . 1992 . 10.4049/jimmunol.148.1.259 . 1530796 . free .
• Fukunaga R, Seto Y, Mizushima S, Nagata S . Three different mRNAs encoding human granulocyte colony-stimulating factor receptor. . Proc. Natl. Acad. Sci. U.S.A. . 87 . 22 . 8702–6 . 1991 . 1701053 . 55027 . 10.1073/pnas.87.22.8702 . free .
• Fukunaga R, Ishizaka-Ikeda E, Pan CX, Seto Y, Nagata S . Functional domains of the granulocyte colony-stimulating factor receptor. . EMBO J. . 10 . 10 . 2855–65 . 1991 . 1717255 . 452996 . 10.1002/j.1460-2075.1991.tb07835.x.
• Inazawa J, Fukunaga R, Seto Y, Nakagawa H, Misawa S, Abe T, Nagata S . Assignment of the human granulocyte colony-stimulating factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3. . Genomics . 10 . 4 . 1075–8 . 1991 . 1833306 . 10.1016/0888-7543(91)90202-P .
• Larsen A, Davis T, Curtis BM, Gimpel S, Sims JE, Cosman D, Park L, Sorensen E, March CJ, Smith CA . Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains. . J. Exp. Med. . 172 . 6 . 1559–70 . 1991 . 2147944 . 2188748 . 10.1084/jem.172.6.1559 .
• Uzumaki H, Okabe T, Sasaki N, Hagiwara K, Takaku F, Tobita M, Yasukawa K, Ito S, Umezawa Y . Identification and characterization of receptors for granulocyte colony-stimulating factor on human placenta and trophoblastic cells. . Proc. Natl. Acad. Sci. U.S.A. . 86 . 23 . 9323–6 . 1990 . 2480598 . 298487 . 10.1073/pnas.86.23.9323 . free .
• Nicholson SE, Oates AC, Harpur AG, Ziemiecki A, Wilks AF, Layton JE . 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 . 8 . 2985–8 . 1994 . 7512720 . 43499 . 10.1073/pnas.91.8.2985 . 1994PNAS...91.2985N . free .
• Dong F, Hoefsloot LH, Schelen AM, Broeders CA, Meijer Y, Veerman AJ, Touw IP, Löwenberg B . Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia. . Proc. Natl. Acad. Sci. U.S.A. . 91 . 10 . 4480–4 . 1994 . 7514305 . 43809 . 10.1073/pnas.91.10.4480 . 1994PNAS...91.4480D . free .
• Dong F, Brynes RK, Tidow N, Welte K, Löwenberg B, Touw IP . 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 . 8 . 487–93 . 1995 . 7542747 . 10.1056/NEJM199508243330804 . 1765/60338 . free .
• Shimoda K, Okamura S, Harada N, Kondo S, Okamura T, Niho Y . Identification of a functional receptor for granulocyte colony-stimulating factor on platelets. . J. Clin. Invest. . 91 . 4 . 1310–3 . 1993 . 7682568 . 288100 . 10.1172/JCI116330 .
• Zhao Y, Wagner F, Frank SJ, Kraft AS . The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte-macrophage colony-stimulating factor receptor beta c chain. . J. Biol. Chem. . 270 . 23 . 13814–8 . 1995 . 7775438 . 10.1074/jbc.270.23.13814 . free .
• Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ . 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 . 11 . 4683–7 . 1994 . 8197119 . 43852 . 10.1073/pnas.91.11.4683 . 1994PNAS...91.4683C . free .
• Haniu M, Horan T, Arakawa T, Le J, Katta V, Rohde MF . Extracellular domain of granulocyte-colony stimulating factor receptor. Interaction with its ligand and identification of a domain in close proximity of ligand-binding region. . Arch. Biochem. Biophys. . 324 . 2 . 344–56 . 1996 . 8554326 . 10.1006/abbi.1995.0047 .
• Horan T, Wen J, Narhi L, Parker V, Garcia A, Arakawa T, Philo J . Dimerization of the extracellular domain of granuloycte-colony stimulating factor receptor by ligand binding: a monovalent ligand induces 2:2 complexes. . Biochemistry . 35 . 15 . 4886–96 . 1996 . 8664280 . 10.1021/bi9525841 .
• McCracken S, Layton JE, Shorter SC, Starkey PM, Barlow DH, Mardon HJ . Expression of granulocyte-colony stimulating factor and its receptor is regulated during the development of the human placenta. . J. Endocrinol. . 149 . 2 . 249–58 . 1996 . 8708536 . 10.1677/joe.0.1490249 .
• Haniu M, Horan T, Arakawa T, Le J, Katta V, Hara S, Rohde MF . Disulfide structure and N-glycosylation sites of an extracellular domain of granulocyte-colony stimulating factor receptor. . Biochemistry . 35 . 40 . 13040–6 . 1996 . 8855939 . 10.1021/bi960213u .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery. . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .

Notes and References

1. Tweardy DJ, Anderson K, Cannizzaro LA, Steinman RA, Croce CM, Huebner K . 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 . Blood . 79 . 5 . 1148–54 . March 1992 . 10.1182/blood.V79.5.1148.1148 . 1371413 . free .
2. Web site: Entrez Gene: CSF3R colony stimulating factor 3 receptor (granulocyte).
3. Mehta HM, Futami M, Glaubach T, Lee DW, Andolina JR, Yang Q, Whichard Z, Quinn M, Lu HF, Kao WM, Przychodzen B, Sarkar CA, Minella A, Maciejewski JP, Corey SJ . Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition . Leukemia . 28 . 5 . 1041–1051 . May 2014 . 24170028 . 5875430 . 10.1038/leu.2013.321 .
4. Zeidler C, Welte K . Kostmann syndrome and severe congenital neutropenia . Semin. Hematol. . 39 . 2 . 82–8 . April 2002 . 11957189 . 10.1053/shem.2002.31913 .
5. Beekman R, Touw IP . G-CSF and its receptor in myeloid malignancy . Blood . 115 . 25 . 5131–6 . June 2010 . 20237318 . 10.1182/blood-2010-01-234120 . free .
6. Ehlers S, Herbst C, Zimmermann M, Scharn N, Germeshausen M, von Neuhoff N, Zwaan CM, Reinhardt K, Hollink IH, Klusmann JH, Lehrnbecher T, Roettgers S, Stary J, Dworzak M, Welte K, Creutzig U, Reinhardt D . Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse . J. Clin. Oncol. . 28 . 15 . 2591–7 . May 2010 . 20406937 . 10.1200/JCO.2009.25.9010 . free .
7. Ward AC, Monkhouse JL, Hamilton JA, Csar XF . Direct binding of Shc, Grb2, SHP-2 and p40 to the murine granulocyte colony-stimulating factor receptor . Biochim. Biophys. Acta . 1448 . 1 . 70–6 . November 1998 . 9824671 . 10.1016/S0167-4889(98)00120-7 . free . 10536/DRO/DU:30096477 . free .
8. Ward AC, Monkhouse JL, Csar XF, Touw IP, Bello PA . 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 . 1 . 117–23 . October 1998 . 9790917 . 10.1006/bbrc.1998.9441 .