Colony stimulating factor 1 receptor: Difference between revisions

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== Clinical significance ==
== 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 = | url = http://ebm.rsmjournals.com/cgi/content/full/229/1/1 }}</ref>  
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 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]].
Mutations in the tyrosine kinase domain have been associated with [[hereditary diffuse leukoencephalopathy with spheroids]].


===As a drug target===
===As a drug target===
Because CSF1R is overexpressed in many cancers and on [[tumor-associated macrophage]]s, '''CSF1R inhibitors''' have been studied for many years as a possible treatment for cancer or inflammatory diseases.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/19689368 ''Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease.'' 2009]</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]]. ([[MCS110]] is a CSF1 inhibitor)
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 to 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>
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==
==Interactions==

Latest revision as of 14:12, 20 August 2018

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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).[1][2] 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.[1]

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.[3][4]

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.[5] 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.[6][7][8]

Mutations in CSF1R are associated with chronic myelomonocytic leukemia and type M4 acute myeloblastic leukemia.[9]

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.[10][11] As of 2017 CSF1R inhibitors in clinical trials include :[11] Pexidartinib, PLX7486, ARRY-382, JNJ-40346527,[12] BLZ945, Emactuzumab, AMG820, IMC-CS4. (PD-0360324 and MCS110 are CSF1 inhibitors)[13]

Another CSF1R inhibitor that targets/depletes TAMs is Cabiralizumab (cabira; FPA-008) which is a monoclonal antibody[14] and is in early clinical trials for metastatic pancreatic cancer.[15][16]

Interactions

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

See also

References

  1. ↑ 1.0 1.1 EntrezGene 1436
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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. PMID 15858070.
  6. ↑ 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.
  7. ↑ 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. doi:10.1073/pnas.91.20.9312. PMC 44802. PMID 7937762.
  8. ↑ 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.
  9. ↑ 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. doi:10.1073/pnas.87.4.1377. JSTOR 2353838. PMC 53478. PMID 2406720.
  10. ↑ Patel S, Player MR (2009). "Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease". Curr Top Med Chem. 9: 599–610. doi:10.2174/156802609789007327. PMID 19689368.
  11. ↑ 11.0 11.1 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.
  12. ↑ 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.
  13. ↑ Interest Builds in CSF1R for Targeting Tumor Microenvironment
  14. ↑ 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).
  15. ↑ A Study of Cabiralzumab Given by Itself or With Nivolumab in Advanced Cancer or Cancer That Has Spread
  16. ↑ Novel Combination Shows Promising Responses in Pancreatic Cancer Nov 2017
  17. ↑ 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.
  18. ↑ 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. PMC 413295. PMID 7681396.
  19. ↑ 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.
  20. ↑ 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.

Further reading

External links

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

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