Colony stimulating factor 1 receptor

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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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