Colony stimulating factor 1 receptor

2018-08-20T14:12:16Z

2605:E000:9149:A600:28EB:F5A8:CD71:723C: gr

{{Infobox_gene}}
'''Colony stimulating factor 1 receptor''' ('''CSF1R'''), also known as '''macrophage colony-stimulating factor receptor''' (M-CSFR), and '''CD115''' ('''C'''luster of '''D'''ifferentiation '''115'''), is a cell-surface [[protein]] encoded, in humans, by the ''CSF1R'' [[gene]] (known also as c-FMS).<ref name="entrez">{{EntrezGene|1436}}</ref><ref name="pmid1611909">{{cite journal |vauthors=Galland F, Stefanova M, Lafage M, Birnbaum D | title = Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15→q23 | journal = Cytogenet. Cell Genet. | volume = 60 | issue = 2 | pages = 114–6 | year = 1992 | pmid = 1611909 | doi = 10.1159/000133316 }}</ref> It is a [[Immune receptor|receptor]] for a [[cytokine]] called [[Macrophage colony-stimulating factor|colony stimulating factor 1]].

==Genomics==

The gene is located on long arm of chromosome 5 (5q32) on the Crick (minus) strand. It is 60.002 kilobases in length. The encoded protein has 972 amino acids and a predicted molecular weight of 107.984 kilo[[Dalton (unit)|Dalton]]s. The first [[intron]] of the ''CSF1R'' gene contains a [[Transcription (genetics)|transcriptionally]] inactive [[RPL7|ribosomal protein L7]] processed [[pseudogene]], oriented in the opposite direction to the ''CSF1R'' gene.<ref name="entrez"/>

== Function ==

The encoded protein is a single pass type I membrane protein and acts as the receptor for [[macrophage colony-stimulating factor|colony stimulating factor 1]], a cytokine which controls the production, [[cell differentiation|differentiation]], and function of [[macrophage]]s. This receptor mediates most, if not all, of the biological effects of this cytokine. [[Ligand (biochemistry)|Ligand]] binding activates CSF1R through a process of [[oligomer]]ization and [[:wikt:trans-|trans-]][[phosphorylation]]. The encoded protein is a [[Receptor tyrosine kinase|tyrosine kinase]] [[transmembrane receptor]] and member of the CSF1/[[PDGF receptor]] family of tyrosine-protein kinases.<ref name="pmid26628682">{{cite journal | vauthors = Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL | title = Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases | journal = Science Signaling | volume = 8 | issue = 405 | pages = rs13 | year = 2015 | pmid = 26628682 | pmc = 4766099 | doi = 10.1126/scisignal.aaa6711 }}</ref><ref name="pmid20137931">{{cite journal | vauthors = Meyers MJ, Pelc M, Kamtekar S, Day J, Poda GI, Hall MK, Michener ML, Reitz BA, Mathis KJ, Pierce BS, Parikh MD, Mischke DA, Long SA, Parlow JJ, Anderson DR, Thorarensen A | display-authors = 6 | title = Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 5 | pages = 1543–7 | year = 2010 | pmid = 20137931 | doi = 10.1016/j.bmcl.2010.01.078 }}</ref>

== Clinical significance ==

Increased levels of CSF1R1 are found in [[microglia]] in [[Alzheimer's disease]] and after brain injuries. The increased receptor expression causes microglia to become more active.<ref name="pmid15858070">{{cite journal |vauthors=Mitrasinovic OM, Grattan A, Robinson CC, Lapustea NB, Poon C, Ryan H, Phong C, Murphy GM | title = Microglia overexpressing the macrophage colony-stimulating factor receptor are neuroprotective in a microglial-hippocampal organotypic coculture system | journal = J. Neurosci. | volume = 25 | issue = 17 | pages = 4442–51 |date=April 2005 | pmid = 15858070 | doi = 10.1523/JNEUROSCI.0514-05.2005 }}</ref> Both CSF1R, and its ligand [[macrophage colony-stimulating factor|colony stimulating factor 1]] play an important role in the development of the [[mammary gland]] and may be involved in the process of mammary gland [[carcinogenesis]].<ref name="pmid18172291">{{cite journal |vauthors=Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, Hankinson SE | title = Circulating colony stimulating factor-1 and breast cancer risk | journal = Cancer Res. | volume = 68 | issue = 1 | pages = 18–21 |date=January 2008 | pmid = 18172291 | pmc = 2821592 | doi = 10.1158/0008-5472.CAN-07-3234 }}</ref><ref name="pmid7937762">{{cite journal |vauthors=Pollard JW, Hennighausen L | title = Colony stimulating factor 1 is required for mammary gland development during pregnancy | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 20 | pages = 9312–6 |date=September 1994 | pmid = 7937762 | pmc = 44802 | doi = 10.1073/pnas.91.20.9312 }}</ref><ref name="pmid14709771">{{cite journal | author = Sapi E | title = The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update | journal = Exp. Biol. Med. (Maywood) | volume = 229 | issue = 1 | pages = 1–11 |date=January 2004 | pmid = 14709771 | doi = 10.1177/153537020422900101| url = http://ebm.rsmjournals.com/cgi/content/full/229/1/1 }}</ref>

Mutations in CSF1R are associated with [[chronic myelomonocytic leukemia]] and type M4 [[acute myeloblastic leukemia]].<ref name="pmid2406720">{{cite journal |vauthors=Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA | title = FMS mutations in myelodysplastic, leukemic, and normal subjects | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 4 | pages = 1377–80 |date=February 1990 | pmid = 2406720 | pmc = 53478 | doi = 10.1073/pnas.87.4.1377 | jstor = 2353838 }}</ref>

Mutations in the tyrosine kinase domain have been associated with [[hereditary diffuse leukoencephalopathy with spheroids]].

===As a drug target===
Because CSF1R is overexpressed in many cancers and on [[tumor-associated macrophage]]s (TAM), '''CSF1R inhibitors''' (and CSF1 inhibitors) have been studied for many years as a possible treatment for cancer or inflammatory diseases.<ref>{{cite journal| pmid=19689368 | volume=9 | title=Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease | year=2009 | journal=Curr Top Med Chem | pages=599–610 | vauthors=Patel S, Player MR | doi=10.2174/156802609789007327}}</ref><ref name="Cannarile_2017">{{cite journal | vauthors = Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D | title = Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy | journal = Journal for Immunotherapy of Cancer | volume = 5 | issue = 1 | pages = 53 | year = 2017 | pmid = 28716061 | pmc = 5514481 | doi = 10.1186/s40425-017-0257-y }}</ref> {{as of|2017}} CSF1R inhibitors in clinical trials include :<ref name="Cannarile_2017" /> [[Pexidartinib]], [[PLX7486]], [[ARRY-382]], [[JNJ-40346527]],<ref name="pmid26233509">{{cite journal | vauthors = Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, Manthey CL, Yan XD, Ge T, Franks C, Greenspan A | title = Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy | journal = The Journal of Rheumatology | volume = 42 | issue = 10 | pages = 1752–60 | year = 2015 | pmid = 26233509 | doi = 10.3899/jrheum.141580 }}</ref> [[BLZ945]], [[Emactuzumab]], [[AMG820]], [[IMC-CS4]]. ([[PD-0360324]] and [[MCS110]] are CSF1 inhibitors)<ref>[https://www.onclive.com/publications/oncology-live/2018/vol-19-no-7/interest-builds-in-csf1r-for-targeting-tumor-microenvironment?p=2 ''Interest Builds in CSF1R for Targeting Tumor Microenvironment'']</ref>

Another CSF1R inhibitor that targets/depletes TAMs is [[Cabiralizumab]] (cabira; FPA-008) which is a [[monoclonal antibody]]<ref>[http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.11078 A phase I/II dose escalation and expansion study of cabiralizumab (cabira; FPA-008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS).]</ref> and is in early clinical trials for metastatic pancreatic cancer.<ref>[https://clinicaltrials.gov/ct2/show/NCT03158272 A Study of Cabiralzumab Given by Itself or With Nivolumab in Advanced Cancer or Cancer That Has Spread]</ref><ref>[http://www.onclive.com/web-exclusives/novel-combination-shows-promising-responses-in-pancreatic-cancer ''Novel Combination Shows Promising Responses in Pancreatic Cancer'' Nov 2017]</ref>

==Interactions==
Colony stimulating factor 1 receptor has been shown to [[Protein-protein interaction|interact]] with:
* [[Cbl gene]],<ref name="pmid11847211">{{cite journal |vauthors=Mancini A, Koch A, Wilms R, Tamura T | title = c-Cbl associates directly with the C-terminal tail of the receptor for the macrophage colony-stimulating factor, c-Fms, and down-modulates this receptor but not the viral oncogene v-Fms | journal = J. Biol. Chem. | volume = 277 | issue = 17 | pages = 14635–40 |date=April 2002 | pmid = 11847211 | doi = 10.1074/jbc.M109214200 }}</ref>
* [[FYN]],<ref name="pmid7681396">{{cite journal |vauthors=Courtneidge SA, Dhand R, Pilat D, Twamley GM, Waterfield MD, Roussel MF | title = Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor | journal = EMBO J. | volume = 12 | issue = 3 | pages = 943–50 |date=March 1993 | pmid = 7681396 | pmc = 413295 | doi = }}</ref>
* [[Grb2]],<ref name="pmid9380408">{{cite journal |vauthors=Mancini A, Niedenthal R, Joos H, Koch A, Trouliaris S, Niemann H, Tamura T | title = Identification of a second Grb2 binding site in the v-Fms tyrosine kinase | journal = Oncogene | volume = 15 | issue = 13 | pages = 1565–72 |date=September 1997 | pmid = 9380408 | doi = 10.1038/sj.onc.1201518 | url = }}</ref>
* [[Suppressor of cytokine signaling 1]],<ref name="pmid11297560">{{cite journal |vauthors=Bourette RP, De Sepulveda P, Arnaud S, Dubreuil P, Rottapel R, Mouchiroud G | title = Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal | journal = J. Biol. Chem. | volume = 276 | issue = 25 | pages = 22133–9 |date=June 2001 | pmid = 11297560 | doi = 10.1074/jbc.M101878200 }}</ref> This receptor is also linked with the cells of MPS.

==See also==
* [[Cluster of differentiation]]
* [[Mouse models of breast cancer metastasis]]
{{Clear}}

==References==
{{reflist|colwidth=35em}}

==Further reading==
{{refbegin|colwidth=35em}}
* {{cite journal |vauthors=Rettenmier CW, Roussel MF, Sherr CJ | title = The colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product) and its ligand | journal = J. Cell Sci. Suppl. | volume = 9 | issue = | pages = 27–44 | year = 1988 | pmid = 2978516 | doi = }}
* {{cite journal |vauthors=Stanley ER, Berg KL, Einstein DB, Lee PS, Pixley FJ, Wang Y, Yeung YG | title = Biology and action of colony--stimulating factor-1 | journal = Mol. Reprod. Dev. | volume = 46 | issue = 1 | pages = 4–10 |date=January 1997 | pmid = 8981357 | doi = 10.1002/(SICI)1098-2795(199701)46:1<4::AID-MRD2>3.0.CO;2-V }}
* {{cite journal |vauthors=Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD | title = Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system | journal = Biochem. J. | volume = 288 | issue = 2| pages = 395–405 |date=December 1992 | pmid = 1334406 | pmc = 1132024 | doi = 10.1042/bj2880395}}
* {{cite journal |vauthors=Boultwood J, Rack K, Kelly S, Madden J, Sakaguchi AY, Wang LM, Oscier DG, Buckle VJ, Wainscoat JS | title = Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 14 | pages = 6176–80 |date=July 1991 | pmid = 1829836 | pmc = 52045 | doi = 10.1073/pnas.88.14.6176 }}
* {{cite journal |vauthors=Roussel MF, Cleveland JL, Shurtleff SA, Sherr CJ | title = Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling | journal = Nature | volume = 353 | issue = 6342 | pages = 361–3 |date=September 1991 | pmid = 1833648 | doi = 10.1038/353361a0 }}
* {{cite journal |vauthors=Reedijk M, Liu XQ, Pawson T | title = Interactions of phosphatidylinositol kinase, GTPase-activating protein (GAP), and GAP-associated proteins with the colony-stimulating factor 1 receptor | journal = Mol. Cell. Biol. | volume = 10 | issue = 11 | pages = 5601–8 |date=November 1990 | pmid = 2172781 | pmc = 361316 | doi = }}
* {{cite journal |vauthors=Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER | title = The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1 | journal = Cell | volume = 41 | issue = 3 | pages = 665–76 |date=July 1985 | pmid = 2408759 | doi = 10.1016/S0092-8674(85)80047-7 }}
* {{cite journal |vauthors=Coussens L, Van Beveren C, Smith D, Chen E, Mitchell RL, Isacke CM, Verma IM, Ullrich A | title = Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus | journal = Nature | volume = 320 | issue = 6059 | pages = 277–80 | year = 1986 | pmid = 2421165 | doi = 10.1038/320277a0 }}
* {{cite journal |vauthors=Hampe A, Shamoon BM, Gobet M, Sherr CJ, Galibert F | title = Nucleotide sequence and structural organization of the human FMS proto-oncogene | journal = Oncogene Res. | volume = 4 | issue = 1 | pages = 9–17 | year = 1989 | pmid = 2524025 | doi = }}
* {{cite journal |vauthors=Visvader J, Verma IM | title = Differential transcription of exon 1 of the human c-fms gene in placental trophoblasts and monocytes | journal = Mol. Cell. Biol. | volume = 9 | issue = 3 | pages = 1336–41 |date=March 1989 | pmid = 2524648 | pmc = 362728 | doi = }}
* {{cite journal |vauthors=Roberts WM, Look AT, Roussel MF, Sherr CJ | title = Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes | journal = Cell | volume = 55 | issue = 4 | pages = 655–61 |date=November 1988 | pmid = 2846185 | doi = 10.1016/0092-8674(88)90224-3 }}
* {{cite journal |vauthors=Xu DQ, Guilhot S, Galibert F | title = Restriction fragment length polymorphism of the human c-fms gene | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 82 | issue = 9 | pages = 2862–5 |date=May 1985 | pmid = 2986142 | pmc = 397666 | doi = 10.1073/pnas.82.9.2862 | jstor = 25278 }}
* {{cite journal |vauthors=Sherr CJ, Rettenmier CW | title = The fms gene and the CSF-1 receptor | journal = Cancer Surv. | volume = 5 | issue = 2 | pages = 221–32 | year = 1986 | pmid = 3022923 | doi = | url = }}
* {{cite journal |vauthors=Le Beau MM, Westbrook CA, Diaz MO, Larson RA, Rowley JD, Gasson JC, Golde DW, Sherr CJ | title = Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders | journal = Science | volume = 231 | issue = 4741 | pages = 984–7 |date=February 1986 | pmid = 3484837 | doi = 10.1126/science.3484837 }}
* {{cite journal |vauthors=Wheeler EF, Roussel MF, Hampe A, Walker MH, Fried VA, Look AT, Rettenmier CW, Sherr CJ | title = The amino-terminal domain of the v-fms oncogene product includes a functional signal peptide that directs synthesis of a transforming glycoprotein in the absence of feline leukemia virus gag sequences | journal = J. Virol. | volume = 59 | issue = 2 | pages = 224–33 |date=August 1986 | pmid = 3525854 | pmc = 253070 | dpi = }}
* {{cite journal |vauthors=Verbeek JS, Roebroek AJ, van den Ouweland AM, Bloemers HP, Van de Ven WJ | title = Human c-fms proto-oncogene: comparative analysis with an abnormal allele | journal = Mol. Cell. Biol. | volume = 5 | issue = 2 | pages = 422–6 |date=February 1985 | pmid = 3974576 | pmc = 366728 | dpi = }}
* {{cite journal |vauthors=Lee AW, Nienhuis AW | title = Mechanism of kinase activation in the receptor for colony-stimulating factor 1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 18 | pages = 7270–4 |date=September 1990 | pmid = 2169623 | pmc = 54725 | doi = 10.1073/pnas.87.18.7270 }}
{{refend}}

==External links==
* {{MeshName|CSF1R+protein,+human}}

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{{Clusters of differentiation}}
{{Cytokine receptors}}
{{Tyrosine kinases}}
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[[Category:Clusters of differentiation]]
[[Category:Immunoglobulin superfamily cytokine receptors]]
[[Category:Tyrosine kinase receptors]]

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Colony stimulating factor 1 receptor