Granulocyte-macrophage colony-stimulating factor receptor

The granulocyte-macrophage colony-stimulating factor receptor, also known as CD116 (Cluster of Differentiation 116), is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells.^[5] In contrast to M-CSF and G-CSF which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on neutrophils, eosinophils and monocytes/macrophages, it is also on CD34+ progenitor cells (myeloblasts) and precursors for erythroid and megakaryocytic lineages, but only in the beginning of their development.^[5][6]

CSF2RA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4NKQ, 4RS1
Identifiers
Aliases	CSF2RA, CD116, CDw116, CSF2R, CSF2RAX, CSF2RAY, CSF2RX, CSF2RY, GM-CSF-R-alpha, GMCSFR, GMR, SMDP4, colony stimulating factor 2 receptor alpha subunit, alphaGMR, colony stimulating factor 2 receptor subunit alpha, GMR-alpha, GMCSFR-alpha, granulocyte-macrophage colony-stimulating factor receptor
External IDs	OMIM: 425000, 306250 MGI: 1339754 HomoloGene: 48406 GeneCards: CSF2RA
Gene location (Human) Chr. X chromosome (human)^[1] Band X;Y Start 1,268,800 bp^[1] End 1,310,381 bp^[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)^[2] Band 19 D3|19 56.89 cM Start 61,223,957 bp^[2] End 61,228,429 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood placenta sural nerve right lung upper lobe of left lung appendix gallbladder bone marrow bone marrow cells Top expressed in superior frontal gyrus blood subcutaneous adipose tissue spleen substantia nigra neural tube lens white adipose tissue adrenal gland islet of Langerhans More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding cytokine receptor activity protein tyrosine kinase activity signaling receptor activity cytokine binding Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane extracellular region intracellular anatomical structure external side of plasma membrane receptor complex Biological process MAPK cascade peptidyl-tyrosine phosphorylation cytokine-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1438 12982 Ensembl ENSG00000198223 ENSMUSG00000059326 UniProt P15509 Q00941 RefSeq (mRNA) NM_001161529 NM_001161530 NM_001161531 NM_001161532 NM_006140 NM_172245 NM_172246 NM_172247 NM_172248 NM_172249 NM_001379153 NM_001379154 NM_001379155 NM_001379156 NM_001379158 NM_001379159 NM_001379160 NM_001379161 NM_001379162 NM_001379163 NM_001379164 NM_001379165 NM_001379166 NM_001379167 NM_001379168 NM_001379169 NM_009970 RefSeq (protein) NP_001155001 NP_001155002 NP_001155003 NP_001155004 NP_006131 NP_758448 NP_758449 NP_758450 NP_758452 NP_001366082 NP_001366083 NP_001366084 NP_001366085 NP_001366087 NP_001366088 NP_001366089 NP_001366090 NP_001366091 NP_001366092 NP_001366093 NP_001366094 NP_001366095 NP_001366096 NP_001366097 NP_001366098 NP_034100 Location (UCSC) Chr X: 1.27 – 1.31 Mb Chr 19: 61.22 – 61.23 Mb PubMed search ^[3] ^[4]
Wikidata
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It is associated with Surfactant metabolism dysfunction type 4.

Structure

The granulocyte-macrophage colony-stimulating factor receptor is a heterodimer composed of at least two different subunits; an α chain, and a β chain which is also present in the receptors for IL-3 and IL-5. The α subunit contains a binding site for granulocyte macrophage colony-stimulating factor, but associates with the ligand only with low affinity.^[6][7] The β chain is involved in signal transduction and formation of high affinity receptor complex together with α chain. Furthermore association of the α and β subunits results in receptor activation.^[8]

α chain

Gene for α chain is in pseudoautosomal region (PAR) of X and Y chromosomes at the very tip of the chromosomes, near telomere regions and also genes encoding IL-3α with which they share some similarities.^[9] Along the gene are several transcription regulatory binding sites with common binding motifs for such transcription factors as GATA, C/EBP or NF-κB.^[6]

α chain is 80kDa type I transmembrane protein composed of 3 domains: extracellular, transmembrane and cytoplasmic. Mature polypeptide contains 378 amino acids - 298 amino acids in extracellular domain, 26 in transmembrane domain, 54 in short cytoplasmic tail, plus 22 amino acid long signal peptide, which is cleaved off during translation.^[6] Extracellular domain contains cytokine receptor domain for binding its cognate ligand with conserved cysteine residues, WSXWS motif and 11 potential N-glycosylation sites for oligosaccharides, which are important for ligand binding and signalling. Cytoplasmic domain is made of short proline-rich motif and has no intrinsic enzymatic activity.^[6][9][10] Similar to such motif is also Box1 sequence in β chain.

β chain

β chain is crucial for enhancement of binding affinity to the ligand and transduces signal of the activated receptor complex. It is shared with other cytokine receptors IL-3 and IL-5.^[9] Its location is on chromosome 22. Surrounding sequences provide binding sites for several regulatory transcription factors similar to those for α chain (GATA, C/EBP, NF-κB).^[6][11] β subunit forms mature 95kDa 800 amino acid long polypeptide with 3 domains: extracellular, transmembrane and cytoplasmic. Extracellular domain contains haematopoietin domains, also known as cytokine receptor modules, which can be found in other cytokine receptors (growth hormone receptor, erythropoietin receptor). In the membrane distant part are typically cysteine residues forming disulphide bonds, proline pair, which devies the extracellular domain into two fibronectin type III-like subdomains in seven stranded β-barrel structure. In the membrane proximal region is then a WSXWS motif as is in α chain.^[6] Cytoplasmic domain serves as a signal transducer.^[9][10]

Structural variants

α chain can be modified in post-transcriptional manner by alternative splicing creating different variant of mRNA. Splicing on 3´end produces transcript where 25 amino acids in C-terminal region are completely replaced by 35 new amino acids. Such protein is functional, but 10 times less abundant. Another splicing variant lacks both transmembrane and cytoplasmic domains. Remaining extracellular domain acts as a soluble GM-CSFRα and have been identified in bone marrow, monocytes and macrophages, placenta and chorio-carcinoma cells. Splicing products on the 5´end were found in primary haematopoietic cells and acute myeloid leukemia blasts.^[6][12]

β subunit can be found in two distinct isoforms: classical full-length protein and alternative form with deletions in transmembrane domain. Deletions results in truncated peptide with 23 original amino acids in the membrane proximal cytoplasmic region and 23 new ones in C-terminal tail. This shorter isoform is unable to transduce any signals, thus acts as a negative inhibitor. Significantly upregulated production is in blasts from acute myeloid leukemia patients.^[6][12]

Signal transduction

Upon dimerisation of the α and β subunits the β subunit becomes phosphorylated on tyrosine residues in its cytoplasmic domain, where are many regions participating in different cell signalling mechanisms for proliferation, differentiation and survival. Formation of high affinity receptor complex includes specific interactions between both subunits and ligand. Interactions then mediate conformational changes and subsequent receptor activation. Receptor is either functional in single heterodimer α1β1 or in dimerised complexes α2β2 joined by intermolecular disulphide bonds.^[6][7][9] For full activation oligomerization of the receptor is crucial, it is formed into hexamer composed of two GM-CSF, two α and two β subunits or dodecamer which is composed of two hexamers.^[11]

Phosphorylation is mediated by tyrosine kinases, members of the Janus kinase (JAK) family, which are constitutively associated with cytoplasmic domain.^[8] Activated kinases then phosphorylate tyrosine residues on cytoplasmic domain of β subunit, thus creating docking sites for Src homology 2 (SH2) domain-containing signalling proteins like Shc and STATs.^[6][11][13] These interactions trigger downstream signalling pathways, depending on the location of phosphorylated tyrosine residues in the chain. Membrane proximal section is known to be responsible for proliferation by activating STAT5 and c-myc.^[6] Membrane distal section is then required for differentiation and survival by prevention of apoptosis and activation of MAPK and PI3K pathways.^[10][11][13]

Downregulation of signal transduction

Simultaneously with receptor activation goes hand in hand its downregulation, that prevents unwanted overactivation. Controlling mechanisms are mainly aimed at inhibition of JAK kinase activity by SHP-1 tyrosine phosphatase with SH2 binding domain or by members of SOCS family which also possess SH2 domain. After direct ligation with JAK kinase, they mediate degradation in proteasome.^[11] Other possibility of downregulation is degradation of phosphorylated β subunit and subsequent internalization of the receptor/ligand complex. Rate of such process positively correlates with amount of ligand/receptor complexes. In addition, after stimulation of β subunit mRNA levels coding α chain decrease and on the contrary expression of soluble α subunit is upregulated. Soluble GM-CSFRα then clutches free ligands with similar affinity as membrane receptor and prevents binding of GM-CSF to the cell surface. GM-CSFRα can be also cleaved off of the membrane receptor.^[6][8]

Role in development

Different expression of GM-CSFR subunits on hematopoietic cells mediates maturation of various lineages. For example in quiescent hematopoietic stem cells the β chain is expressed at very low levels and the amount increases along initial differentiation of erythroid, megakaryocytic, granulocytic and monocytic lineages. In the first two mentioned lineages the expression eventually vanishes completely, in granulocytes and monocytes persists and continues to grow during their differentiation. In monocytes and mainly neutrophils receptor regulates proliferation, maturation and overall survival.^[6][11]

Kinetics of the receptor in immature and mature myeloid cells in response to GM-CSF is readily regulated by internalization or just by above mentioned degradation and desensitization of β subunit (mainly in the earlier hematopoietic development).^[6]

Role in malaria pathogenesis

It was shown that defective dendritic cell (DC) differentiation in malaria at least partially caused by GM-CSFR dysregulation and GM-CSFR modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit.^[14][15]

References

1. GRCh38: Ensembl release 89: ENSG00000198223 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000059326 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Nicola NA, Metcalf D (Aug 1985). "Binding of 125I-labeled granulocyte colony-stimulating factor to normal murine hemopoietic cells". Journal of Cellular Physiology. 124 (2): 313–21. doi:10.1002/jcp.1041240222. PMID 3876343. S2CID 3054917.
6. Barreda, Daniel R.; Hanington, Patrick C.; Belosevic, Miodrag (2004-05-03). "Regulation of myeloid development and function by colony stimulating factors". Developmental and Comparative Immunology. 28 (5): 509–554. doi:10.1016/j.dci.2003.09.010. ISSN 0145-305X. PMID 15062647.
7. McClure BJ, Hercus TR, Cambareri BA, Woodcock JM, Bagley CJ, Howlett GJ, Lopez AF (Feb 2003). "Molecular assembly of the ternary granulocyte-macrophage colony-stimulating factor receptor complex". Blood. 101 (4): 1308–15. doi:10.1182/blood-2002-06-1903. PMID 12393492.
8. Geijsen N, Koenderman L, Coffer PJ (Mar 2001). "Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family". Cytokine & Growth Factor Reviews. 12 (1): 19–25. doi:10.1016/S1359-6101(00)00019-8. PMID 11312115.
9. Broughton, Sophie E.; Dhagat, Urmi; Hercus, Timothy R.; Nero, Tracy L.; Grimbaldeston, Michele A.; Bonder, Claudine S.; Lopez, Angel F.; Parker, Michael W. (November 2012). "The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling". Immunological Reviews. 250 (1): 277–302. doi:10.1111/j.1600-065X.2012.01164.x. ISSN 1600-065X. PMID 23046136. S2CID 11220164.
10. Hercus, Timothy R.; Broughton, Sophie E.; Ekert, Paul G.; Ramshaw, Hayley S.; Perugini, Michelle; Grimbaldeston, Michele; Woodcock, Joanna M.; Thomas, Daniel; Pitson, Stuart; Hughes, Timothy; D'Andrea, Richard J. (April 2012). "The GM-CSF receptor family: mechanism of activation and implications for disease". Growth Factors. 30 (2): 63–75. doi:10.3109/08977194.2011.649919. ISSN 1029-2292. PMID 22257375. S2CID 3141435.
11. Lopez, Angel F.; Hercus, Timothy R.; Ekert, Paul; Littler, Dene R.; Guthridge, Mark; Thomas, Daniel; Ramshaw, Hayley S.; Stomski, Frank; Perugini, Michelle; D'Andrea, Richard; Grimbaldeston, Michele (July 2010). "Molecular basis of cytokine receptor activation". IUBMB Life. 62 (7): 509–518. doi:10.1002/iub.350. ISSN 1521-6551. PMID 20540154.
12. Faderl, Stefan; Harris, David; Van, Quin; Kantarjian, Hagop M.; Talpaz, Moshe; Estrov, Zeev (2003-07-15). "Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia". Blood. 102 (2): 630–637. doi:10.1182/blood-2002-06-1890. ISSN 0006-4971. PMID 12663443.
13. Doyle SE, Gasson JC (Aug 1998). "Characterization of the role of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit in the activation of JAK2 and STAT5". Blood. 92 (3): 867–76. doi:10.1182/blood.V92.3.867. PMID 9680354.
14. Skorokhod O, Schwarzer E, Grune T, Arese P (2005). "Role of 4-hydroxynonenal in the hemozoin-mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4". Biofactors. 24 (1–4): 283–9. doi:10.1002/biof.5520240133. PMID 16403989. S2CID 35090757.
15. Skorokhod O, Barrera V, Mandili G, Costanza F, Valente E, Ulliers D, Schwarzer E (2021). "Malaria Pigment Hemozoin Impairs GM-CSF Receptor Expression and Function by 4-Hydroxynonenal". Antioxidants. 10 (8): 1259. doi:10.3390/antiox10081259. PMC 8389202. PMID 34439507.

Further reading

• Rappold G, Willson TA, Henke A, Gough NM (Oct 1992). "Arrangement and localization of the human GM-CSF receptor alpha chain gene CSF2RA within the X-Y pseudoautosomal region". Genomics. 14 (2): 455–61. doi:10.1016/S0888-7543(05)80241-1. PMID 1358805.
• Hayashida K, Kitamura T, Gorman DM, Arai K, Yokota T, Miyajima A (Dec 1990). "Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor". Proceedings of the National Academy of Sciences of the United States of America. 87 (24): 9655–9. Bibcode:1990PNAS...87.9655H. doi:10.1073/pnas.87.24.9655. PMC 55231. PMID 1702217.
• Crosier KE, Wong GG, Mathey-Prevot B, Nathan DG, Sieff CA (Sep 1991). "A functional isoform of the human granulocyte/macrophage colony-stimulating factor receptor has an unusual cytoplasmic domain". Proceedings of the National Academy of Sciences of the United States of America. 88 (17): 7744–8. Bibcode:1991PNAS...88.7744C. doi:10.1073/pnas.88.17.7744. PMC 52379. PMID 1715577.
• Raines MA, Liu L, Quan SG, Joe V, DiPersio JF, Golde DW (Sep 1991). "Identification and molecular cloning of a soluble human granulocyte-macrophage colony-stimulating factor receptor". Proceedings of the National Academy of Sciences of the United States of America. 88 (18): 8203–7. Bibcode:1991PNAS...88.8203R. doi:10.1073/pnas.88.18.8203. PMC 52475. PMID 1832774.
• Gough NM, Gearing DP, Nicola NA, Baker E, Pritchard M, Callen DF, Sutherland GR (Jun 1990). "Localization of the human GM-CSF receptor gene to the X-Y pseudoautosomal region". Nature. 345 (6277): 734–6. Bibcode:1990Natur.345..734G. doi:10.1038/345734a0. PMID 1972780. S2CID 4309152.
• Ashworth A, Kraft A (Dec 1990). "Cloning of a potentially soluble receptor for human GM-CSF". Nucleic Acids Research. 18 (23): 7178. doi:10.1093/nar/18.23.7178. PMC 332824. PMID 2148207.
• Gearing DP, King JA, Gough NM, Nicola NA (Dec 1989). "Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor". The EMBO Journal. 8 (12): 3667–76. doi:10.1002/j.1460-2075.1989.tb08541.x. PMC 402049. PMID 2555171.
• DiPersio J, Billing P, Kaufman S, Eghtesady P, Williams RE, Gasson JC (Feb 1988). "Characterization of the human granulocyte-macrophage colony-stimulating factor receptor". The Journal of Biological Chemistry. 263 (4): 1834–41. doi:10.1016/S0021-9258(19)77952-6. PMID 2828352.
• Williams WV, VonFeldt JM, Rosenbaum H, Ugen KE, Weiner DB (Oct 1994). "Molecular cloning of a soluble form of the granulocyte-macrophage colony-stimulating factor receptor alpha chain from a myelomonocytic cell line. Expression, biologic activity, and preliminary analysis of transcript distribution". Arthritis and Rheumatism. 37 (10): 1468–78. doi:10.1002/art.1780371010. PMID 7945472.
• Jubinsky PT, Laurie AS, Nathan DG, Yetz-Aldepe J, Sieff CA (Dec 1994). "Expression and function of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit". Blood. 84 (12): 4174–85. doi:10.1182/blood.V84.12.4174.bloodjournal84124174. PMID 7994031.
• Hu X, Emanuel PD, Zuckerman KS (Sep 1994). "Cloning and sequencing of the cDNAs encoding two alternative splicing-derived variants of the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1223 (2): 306–8. doi:10.1016/0167-4889(94)90241-0. PMID 8086503.
• Nakagawa Y, Kosugi H, Miyajima A, Arai K, Yokota T (Apr 1994). "Structure of the gene encoding the alpha subunit of the human granulocyte-macrophage colony stimulating factor receptor. Implications for the evolution of the cytokine receptor superfamily". The Journal of Biological Chemistry. 269 (14): 10905–12. doi:10.1016/S0021-9258(17)34144-3. PMID 8144676.
• Zhao Y, Rong H, Chegini N (Oct 1995). "Expression and selective cellular localization of granulocyte-macrophage colony-stimulating factor (GM-CSF) and GM-CSF alpha and beta receptor messenger ribonucleic acid and protein in human ovarian tissue". Biology of Reproduction. 53 (4): 923–30. doi:10.1095/biolreprod53.4.923. PMID 8547489.
• Lia F, Rajotte D, Clark SC, Hoang T (Nov 1996). "A dominant negative granulocyte-macrophage colony-stimulating factor receptor alpha chain reveals the multimeric structure of the receptor complex". The Journal of Biological Chemistry. 271 (45): 28287–93. doi:10.1074/jbc.271.45.28287. PMID 8910448.
• Wei S, Liu JH, Epling-Burnette PK, Gamero AM, Ussery D, Pearson EW, Elkabani ME, Diaz JI, Djeu JY (Dec 1996). "Critical role of Lyn kinase in inhibition of neutrophil apoptosis by granulocyte-macrophage colony-stimulating factor". Journal of Immunology. 157 (11): 5155–62. doi:10.4049/jimmunol.157.11.5155. PMID 8943427. S2CID 42022045.
• Soldi R, Primo L, Brizzi MF, Sanavio F, Aglietta M, Polentarutti N, Pegoraro L, Mantovani A, Bussolino F (Feb 1997). "Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor". Blood. 89 (3): 863–72. doi:10.1182/blood.V89.3.863. PMID 9028317.
• Matsuguchi T, Zhao Y, Lilly MB, Kraft AS (Jul 1997). "The cytoplasmic domain of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit is essential for both GM-CSF-mediated growth and differentiation". The Journal of Biological Chemistry. 272 (28): 17450–9. doi:10.1074/jbc.272.28.17450. PMID 9211889.
• Rivas CI, Vera JC, Delgado-López F, Heaney ML, Guaiquil VH, Zhang RH, Scher HI, Concha II, Nualart F, Cordon-Cardo C, Golde DW (Feb 1998). "Expression of granulocyte-macrophage colony-stimulating factor receptors in human prostate cancer". Blood. 91 (3): 1037–43. doi:10.1182/blood.V91.3.1037. PMID 9446667.
• Hu X, Zuckerman KS (Jun 1998). "Cloning and sequencing of an alternative splicing-derived cDNA variant of the GM-CSF receptor alpha subunit, which encodes a truncated protein". American Journal of Hematology. 58 (2): 145–7. doi:10.1002/(SICI)1096-8652(199806)58:2<145::AID-AJH11>3.0.CO;2-A. PMID 9625584.
• Taha RA, Leung DY, Ghaffar O, Boguniewicz M, Hamid Q (Aug 1998). "In vivo expression of cytokine receptor mRNA in atopic dermatitis". The Journal of Allergy and Clinical Immunology. 102 (2): 245–50. doi:10.1016/S0091-6749(98)70093-4. PMID 9723668.

External links

• GM-CSF+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)