Colony stimulating factor 1 receptor

CSF1R
Available structures
PDB	Ortholog search: PDBe RCSB
showList of PDB id codes
	2I0V, 2I0Y, 2I1M, 2OGV, 3BEA, 3DPK, 3KRJ, 3KRL, 3LCD, 3LCO, 4DKD, 4HW7, 4LIQ, 4R7H, 4R7I, 4WRL, 4WRM
Identifiers
Aliases	CSF1R, C-FMS, CD115, CSF-1R, CSFR, FIM2, FMS, HDLS, M-CSF-R, colony stimulating factor 1 receptor, BANDDOS
External IDs	OMIM: 164770 MGI: 1339758 HomoloGene: 3817 GeneCards: CSF1R
EC number	2.7.10.1
showGene location (Human)
Chr.	Chromosome 5 (human)
End	150,113,372 bp
showGene location (Mouse)
Chr.	Chromosome 18 (mouse)
End	61,132,149 bp
showRNA expression pattern
	More reference expression data
showGene ontology
Molecular function	• nucleotide binding; • protein tyrosine kinase activity; • protein kinase activity; • transferase activity; • transmembrane receptor protein tyrosine kinase activity; • kinase activity; • protein homodimerization activity; • ATP binding; • protein phosphatase binding; • macrophage colony-stimulating factor receptor activity; • cytokine binding; • GO:0001948 protein binding; • receptor tyrosine kinase; • transmembrane signaling receptor activity;
Cellular component	• integral component of membrane; • integral component of plasma membrane; • membrane; • cell surface; • CSF1-CSF1R complex; • nucleoplasm; • plasma membrane; • intracellular membrane-bounded organelle; • cytoplasm; • receptor complex;
Biological process	• negative regulation of cell population proliferation; • transmembrane receptor protein tyrosine kinase signaling pathway; • positive regulation of protein serine/threonine kinase activity; • mammary gland duct morphogenesis; • positive regulation of cell motility; • macrophage colony-stimulating factor signaling pathway; • phosphatidylinositol-mediated signaling; • negative regulation of apoptotic process; • positive regulation of ERK1 and ERK2 cascade; • signal transduction; • axon guidance; • multicellular organism development; • monocyte differentiation; • macrophage differentiation; • ruffle organization; • positive regulation of cell migration; • cellular response to cytokine stimulus; • protein autophosphorylation; • peptidyl-tyrosine phosphorylation; • olfactory bulb development; • regulation of bone resorption; • phosphatidylinositol metabolic process; • protein phosphorylation; • positive regulation of protein tyrosine kinase activity; • cell-cell junction maintenance; • osteoclast differentiation; • innate immune response; • regulation of actin cytoskeleton reorganization; • immune system process; • inflammatory response; • positive regulation of protein phosphorylation; • forebrain neuron differentiation; • phosphorylation; • cellular response to macrophage colony-stimulating factor stimulus; • positive regulation of cell population proliferation; • regulation of cell shape; • cell population proliferation; • positive regulation of tyrosine phosphorylation of STAT protein; • cytokine-mediated signaling pathway; • hemopoiesis; • negative regulation of signal transduction; • cell differentiation; • hematopoietic progenitor cell differentiation; • positive regulation of MAPK cascade; • response to ischemia; • microglial cell proliferation; • positive regulation by host of viral process;
	Sources:Amigo / QuickGO
Orthologs
	1436
	12978
	ENSG00000182578
	ENSMUSG00000024621
	P07333
	P09581
	NM_001288705; NM_005211; NM_001349736; NM_001375320; NM_001375321
	NM_001037859; NM_007779
	NP_001275634; NP_005202; NP_001336665; NP_001362249; NP_001362250
	NP_001032948
	Wikidata
View/Edit Human	View/Edit Mouse

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded, in humans, by the CSF1R gene (known also as c-FMS).^[5]^[6] It is a receptor for a cytokine called 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 kiloDaltons. The first intron of the CSF1R gene contains a transcriptionally inactive ribosomal protein L7 processed pseudogene, oriented in the opposite direction to the CSF1R gene.^[5]

Function[]

The encoded protein is a single pass type I membrane protein and acts as the receptor for colony stimulating factor 1, a cytokine which controls the production, differentiation, and function of macrophages. This receptor mediates most, if not all, of the biological effects of this cytokine. Ligand binding activates CSF1R through a process of oligomerization and trans-phosphorylation. The encoded protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases.^[7]^[8]

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.^[9] Both CSF1R, and its ligand 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.^[10]^[11]^[12]

Mutations in CSF1R are associated with chronic myelomonocytic leukemia and type M4 acute myeloblastic leukemia.^[13]

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 macrophages (TAM), CSF1R inhibitors (and CSF1 inhibitors) have been studied for many years as a possible treatment for cancer or inflammatory diseases.^[14]^[15] As of 2017 CSF1R inhibitors in clinical trials include :^[15] Pexidartinib, PLX7486, , JNJ-40346527,^[16] , Emactuzumab, , . ( and are CSF1 inhibitors)^[17]

Another CSF1R inhibitor that targets/depletes TAMs is Cabiralizumab (cabira; FPA-008) which is a monoclonal antibody^[18] and is in early clinical trials for metastatic pancreatic cancer.^[19]^[20]

Interactions[]

Colony stimulating factor 1 receptor has been shown to interact with:

Cbl gene,^[21]
FYN,^[22]
Grb2,^[23]
Suppressor of cytokine signaling 1,^[24] This receptor is also linked with the cells of MPS.

References[]

^ Jump up to: ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000182578 - Ensembl, May 2017
^ Jump up to: ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000024621 - Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Jump up to: ^a ^b EntrezGene 1436
^ Galland F, Stefanova M, Lafage M, Birnbaum D (1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15→q23". Cytogenet. Cell Genet. 60 (2): 114–6. doi:10.1159/000133316. PMID 1611909.
^ Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL (2015). "Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases". Science Signaling. 8 (405): rs13. doi:10.1126/scisignal.aaa6711. PMC 4766099. PMID 26628682.
^ Meyers MJ, Pelc M, Kamtekar S, Day J, Poda GI, Hall MK, et al. (2010). "Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode". Bioorganic & Medicinal Chemistry Letters. 20 (5): 1543–7. doi:10.1016/j.bmcl.2010.01.078. PMID 20137931.
^ Mitrasinovic OM, Grattan A, Robinson CC, Lapustea NB, Poon C, Ryan H, Phong C, Murphy GM (April 2005). "Microglia overexpressing the macrophage colony-stimulating factor receptor are neuroprotective in a microglial-hippocampal organotypic coculture system". J. Neurosci. 25 (17): 4442–51. doi:10.1523/JNEUROSCI.0514-05.2005. PMC 6725106. PMID 15858070.
^ Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, Hankinson SE (January 2008). "Circulating colony stimulating factor-1 and breast cancer risk". Cancer Res. 68 (1): 18–21. doi:10.1158/0008-5472.CAN-07-3234. PMC 2821592. PMID 18172291.
^ Pollard JW, Hennighausen L (September 1994). "Colony stimulating factor 1 is required for mammary gland development during pregnancy". Proc. Natl. Acad. Sci. U.S.A. 91 (20): 9312–6. Bibcode:1994PNAS...91.9312P. doi:10.1073/pnas.91.20.9312. PMC 44802. PMID 7937762.
^ Sapi E (January 2004). "The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update". Exp. Biol. Med. (Maywood). 229 (1): 1–11. doi:10.1177/153537020422900101. PMID 14709771. S2CID 30541196. Archived from the original on 2011-07-24. Retrieved 2011-05-09.
^ Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA (February 1990). "FMS mutations in myelodysplastic, leukemic, and normal subjects". Proc. Natl. Acad. Sci. U.S.A. 87 (4): 1377–80. Bibcode:1990PNAS...87.1377R. doi:10.1073/pnas.87.4.1377. JSTOR 2353838. PMC 53478. PMID 2406720.
^ Patel S, Player MR (2009). "Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease". Curr Top Med Chem. 9 (7): 599–610. doi:10.2174/156802609789007327. PMID 19689368.
^ Jump up to: ^a ^b Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D (2017). "Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy". Journal for Immunotherapy of Cancer. 5 (1): 53. doi:10.1186/s40425-017-0257-y. PMC 5514481. PMID 28716061.
^ Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, Manthey CL, Yan XD, Ge T, Franks C, Greenspan A (2015). "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". The Journal of Rheumatology. 42 (10): 1752–60. doi:10.3899/jrheum.141580. PMID 26233509.
^ Interest Builds in CSF1R for Targeting Tumor Microenvironment
^ 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).
^ A Study of Cabiralzumab Given by Itself or With Nivolumab in Advanced Cancer or Cancer That Has Spread
^ Novel Combination Shows Promising Responses in Pancreatic Cancer Nov 2017
^ Mancini A, Koch A, Wilms R, Tamura T (April 2002). "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". J. Biol. Chem. 277 (17): 14635–40. doi:10.1074/jbc.M109214200. PMID 11847211.
^ Courtneidge SA, Dhand R, Pilat D, Twamley GM, Waterfield MD, Roussel MF (March 1993). "Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor". EMBO J. 12 (3): 943–50. doi:10.1002/j.1460-2075.1993.tb05735.x. PMC 413295. PMID 7681396.
^ Mancini A, Niedenthal R, Joos H, Koch A, Trouliaris S, Niemann H, Tamura T (September 1997). "Identification of a second Grb2 binding site in the v-Fms tyrosine kinase". Oncogene. 15 (13): 1565–72. doi:10.1038/sj.onc.1201518. PMID 9380408.
^ Bourette RP, De Sepulveda P, Arnaud S, Dubreuil P, Rottapel R, Mouchiroud G (June 2001). "Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal". J. Biol. Chem. 276 (25): 22133–9. doi:10.1074/jbc.M101878200. PMID 11297560.

External links[]

CSF1R+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] Jump up to: ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000182578 - Ensembl, May 2017

[refGRCm38Ensembl-2] Jump up to: ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000024621 - 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.

[entrez-5] Jump up to: ^a ^b EntrezGene 1436

[pmid1611909-6] Galland F, Stefanova M, Lafage M, Birnbaum D (1992). "Localization of the 5' end of the MCF2 oncogene to human chromosome 15q15→q23". Cytogenet. Cell Genet. 60 (2): 114–6. doi:10.1159/000133316. PMID 1611909.

[pmid26628682-7] Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL (2015). "Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases". Science Signaling. 8 (405): rs13. doi:10.1126/scisignal.aaa6711. PMC 4766099. PMID 26628682.

[pmid20137931-8] Meyers MJ, Pelc M, Kamtekar S, Day J, Poda GI, Hall MK, et al. (2010). "Structure-based drug design enables conversion of a DFG-in binding CSF-1R kinase inhibitor to a DFG-out binding mode". Bioorganic & Medicinal Chemistry Letters. 20 (5): 1543–7. doi:10.1016/j.bmcl.2010.01.078. PMID 20137931.

[pmid15858070-9] Mitrasinovic OM, Grattan A, Robinson CC, Lapustea NB, Poon C, Ryan H, Phong C, Murphy GM (April 2005). "Microglia overexpressing the macrophage colony-stimulating factor receptor are neuroprotective in a microglial-hippocampal organotypic coculture system". J. Neurosci. 25 (17): 4442–51. doi:10.1523/JNEUROSCI.0514-05.2005. PMC 6725106. PMID 15858070.

[pmid18172291-10] Tamimi RM, Brugge JS, Freedman ML, Miron A, Iglehart JD, Colditz GA, Hankinson SE (January 2008). "Circulating colony stimulating factor-1 and breast cancer risk". Cancer Res. 68 (1): 18–21. doi:10.1158/0008-5472.CAN-07-3234. PMC 2821592. PMID 18172291.

[pmid7937762-11] Pollard JW, Hennighausen L (September 1994). "Colony stimulating factor 1 is required for mammary gland development during pregnancy". Proc. Natl. Acad. Sci. U.S.A. 91 (20): 9312–6. Bibcode:1994PNAS...91.9312P. doi:10.1073/pnas.91.20.9312. PMC 44802. PMID 7937762.

[pmid14709771-12] Sapi E (January 2004). "The role of CSF-1 in normal physiology of mammary gland and breast cancer: an update". Exp. Biol. Med. (Maywood). 229 (1): 1–11. doi:10.1177/153537020422900101. PMID 14709771. S2CID 30541196. Archived from the original on 2011-07-24. Retrieved 2011-05-09.

[pmid2406720-13] Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA (February 1990). "FMS mutations in myelodysplastic, leukemic, and normal subjects". Proc. Natl. Acad. Sci. U.S.A. 87 (4): 1377–80. Bibcode:1990PNAS...87.1377R. doi:10.1073/pnas.87.4.1377. JSTOR 2353838. PMC 53478. PMID 2406720.

[14] Patel S, Player MR (2009). "Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease". Curr Top Med Chem. 9 (7): 599–610. doi:10.2174/156802609789007327. PMID 19689368.

[Cannarile_2017-15] Jump up to: ^a ^b Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D (2017). "Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy". Journal for Immunotherapy of Cancer. 5 (1): 53. doi:10.1186/s40425-017-0257-y. PMC 5514481. PMID 28716061.

[pmid26233509-16] Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, Manthey CL, Yan XD, Ge T, Franks C, Greenspan A (2015). "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". The Journal of Rheumatology. 42 (10): 1752–60. doi:10.3899/jrheum.141580. PMID 26233509.

[17] Interest Builds in CSF1R for Targeting Tumor Microenvironment

[18] 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).

[19] A Study of Cabiralzumab Given by Itself or With Nivolumab in Advanced Cancer or Cancer That Has Spread

[20] Novel Combination Shows Promising Responses in Pancreatic Cancer Nov 2017

[pmid11847211-21] Mancini A, Koch A, Wilms R, Tamura T (April 2002). "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". J. Biol. Chem. 277 (17): 14635–40. doi:10.1074/jbc.M109214200. PMID 11847211.

[pmid7681396-22] Courtneidge SA, Dhand R, Pilat D, Twamley GM, Waterfield MD, Roussel MF (March 1993). "Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor". EMBO J. 12 (3): 943–50. doi:10.1002/j.1460-2075.1993.tb05735.x. PMC 413295. PMID 7681396.

[pmid9380408-23] Mancini A, Niedenthal R, Joos H, Koch A, Trouliaris S, Niemann H, Tamura T (September 1997). "Identification of a second Grb2 binding site in the v-Fms tyrosine kinase". Oncogene. 15 (13): 1565–72. doi:10.1038/sj.onc.1201518. PMID 9380408.

[pmid11297560-24] Bourette RP, De Sepulveda P, Arnaud S, Dubreuil P, Rottapel R, Mouchiroud G (June 2001). "Suppressor of cytokine signaling 1 interacts with the macrophage colony-stimulating factor receptor and negatively regulates its proliferation signal". J. Biol. Chem. 276 (25): 22133–9. doi:10.1074/jbc.M101878200. PMID 11297560.

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show v t Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1–50	CD1 a-c 1A 1B 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50
51–100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100
101–150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150
151–200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200
201–250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249
251–300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299
301–350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

show v t Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)