Colony stimulating factor 1 receptor
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Location (UCSC) | Chr 5: 150.05 – 150.11 Mb | Chr 18: 61.23 – 61.27 Mb | |||||||
PubMed search | [3] | [4] |
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
Gene
In the human genome, the CSF1R gene is located on chromosome 5 (5q32), and in mice the Csf1r gene is located on chromosome 18 (18D). CSF1R is 60.002 kilobases (kbs) in length.
Protein
CSF1R, the protein encoded by the CSF1R gene is a
Protein | Full protein name; function |
---|---|
SFK | Src family tyrosine kinases |
Grb2 | Adaptor |
Mona | Monocyte adaptor; adaptor |
Socs1
|
Suppressor of cytokine signaling-1; adaptor |
PLCγ
|
Phospholipase C-γ |
p85 PI3K | Regulatory subunit of PI3K |
Cbl | Casitas B lineage; ubiquitin ligase, adaptor |
FMIP
|
FMS-interacting protein; function unknown |
PP2A
|
Protein phosphatase 2A; serine/threonine phosphatase |
Pyk2
|
Proline-rich and Ca2C-activated tyrosine kinase |
Paxilin | Focal complex adaptor |
PTPφ
|
PTP for phosphopaxillin |
MAYP/PSTPIP2 | Macrophage actin-associated and tyrosine-phosphorylated protein; actin bundling |
Iba1
|
Ionized Ca2C-binding adaptor protein 1; actin bundling |
Gab2 | Grb2-associated binder-2; Adaptor |
Gab3
|
Grb2-associated binder-3; adaptor |
SHIP1
|
SH2-domain-containing polyinositol phosphatase-1 |
SHP1
|
SH2-domain-containing phosphatase-1; PTP |
SHP2
|
SH2-domain-containing phosphatase-2; PTP |
PKC-δ
|
Protein kinase C-d |
Pkare
|
PKA-related gene (Pkare); protein kinase |
MysPDZ
|
110-kDa myosin XVIIIA |
STAT1, STAT3, STAT5 | Signal transducers and activators of transcription-1, -2, -3; transcription factors |
Dok1, Dok2, Dok3 | Downstream of kinase-1, -2, -3; adaptors |
Vav | Rho family guanine-nucleotide-exchange factor |
BLIMP-1
|
B-lymphocyte-induced maturation protein-1; transcriptional repressor |
Function
Osteoclasts
Osteoclast are multi-nucleated cells that that absorb and remove bone which is critical for growth of new bones and maintenance of bone strength. Osteoclasts are critical for the bone remodeling cycle which is achieved by the building of bone by osteoblasts, reabsorption by osteoclasts, and remodeling by osteoblasts.[10] Osteoclasts precursor cells and mature osteoclast require stimulation of CSF1R for survival. Blockage of CSF1R signaling prevents osteoclast precursor cells from proliferating, maturing, and fusing into multi-nucleated cells. Stimulation of CSF1R promotes osteoclastogenesis (differentiation of monocytes into osteoclasts). CSF1R signaling in osteoclasts precursors promotes survival by upregulation of the Bcl-X(L) protein, an inhibitor of pro-apoptotic caspase-9. CSF1R signaling in mature osteoclasts promotes survival by stimulating mTOR/S6 kinase and the Na/HCO3 co-transporter, NBCn1.[11] CSF1R signaling also directly regulates osteoclast function. Osteoclasts migrate along the bone surface, then adhere to the bone to degrade and reabsorb the bone matrix. CSF1R signaling positively regulates this behavior, increasing osteoclast chemotaxis and bone reabsorption.[10]
Monocytes and macrophages
Monocytes and macrophages are
Microglia
Neural progenitor cells
CSF1R signaling has been found to play important roles in non-myeloid cells such as neural progenitor cells,
Germline cells
CSF1R is expressed in oocytes, the trophoblast, and fertilized embryos prior to implantation in the uterus.[8] Studies using early mouse embryos in vitro have shown that activation of CSF1R stimulates formation of the blastocyst cavity and enhances the number of trophoblast cells. Csf1r loss-of-function mice exhibit several reproductive system abnormalities in the estrous cycle and ovulation rates as well as reduced antral follicles and ovarian macrophages. It is not clear whether ovulation dysfunction in Csf1r loss-of-function mice is due to loss of the protective effects of ovarian macrophages or loss of CSF1R signaling in oocytes themselves.[11]
Clinical significance
This section needs to be updated.(August 2019) |
Bone disease
Cancer
Neurological disorders
Adult-onset leukoencephalopathy
Because of the importance of the CSF1R gene in myeloid cell survival, maturation, and function, loss-of-function in both inherited copies of the CSF1R gene causes postnatal mortality.
Other brain diseases and disorders
CSF1R signaling is involved in several diseases and disorders of the
Therapeutics
Because
Drug name | Form | Targets | Clinical trial diseases |
---|---|---|---|
Pexidartinib (PLX3397) | Small molecule | CSF1R, Flt3
|
acral melanoma, mucosal melanoma
|
Imatinib | Small molecule | CSF1R, PDGFR-β
|
chronic myeloid leukemia (CML), breast cancer
|
PLX5622 | Small molecule | CSF1R | Rheumatoid arthritis, cancer, neuropathic pain, Alzheimer's disease |
Sotuletinib (BLZ945) | Small molecule | CSF1R, c-KIT, PDGFRβ, and Flt3 | amyotrophic lateral sclerosis
|
GW2580 | Small molecule | CSF1R | Arthritis, osteoporosis, cancer |
Ki20227 | Small molecule | CSF1R, VEGFR2, c-KIT, and PDGFRβ | Osteolysis, breast cancer |
Edicotinib
(JNJ-40346527) |
Small molecule | CSF1R, c-KIT, and Flt3 | Alzheimer's disease, cHL, rheumatoid arthritis, neurodegenerative diseases |
Emactuzumab (RG7155) | Monoclonal antibody | CSF1R | Solid tumors |
IMC-CS4 (LY3022855) | Monoclonal antibody | CSF1R | Solid tumors, breast cancer, prostate cancer |
AMG820 | Monoclonal antibody | CSF1R | Solid tumors |
Safety of CSF1R inhibition
The safety of CSF1R inhibitors has been extensively characterized in
Controversy
CSF1R inhibitors such as PLX5622 are widely used to study the role of microglia in mouse
Interactions
Colony stimulating factor 1 receptor has been shown to
- Cbl gene,[27]
- FYN,[28]
- Grb2,[29]
- Suppressor of cytokine signaling 1,[30] This receptor is also linked with the cells of MPS.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000182578 – Ensembl, May 2017
- ^ 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.
- ^ a b EntrezGene 1436
- PMID 1611909.
- ^ PMID 24890514.
- ^ PMID 32801364.
- ^ PMID 15519852.
- ^ PMID 29293000.
- ^ PMID 28236968.
- ^ PMID 27083478.
- ^ PMID 32792173.
- PMID 28569732.
- PMID 23136547.
- ^ PMID 28716061.
- PMID 2406720.
- PMID 28768545.
- S2CID 4943986.
- S2CID 14832382.
- S2CID 52822422.
- PMID 33127097.
- S2CID 222080969.
- ^ Center for Drug Evaluation and Research (2019-12-20). "FDA approves pexidartinib for tenosynovial giant cell tumor". FDA.
- PMID 33446486.
- PMID 33446487.
- PMID 11847211.
- PMID 7681396.
- PMID 9380408.
- PMID 11297560.
Further reading
- Rettenmier CW, Roussel MF, Sherr CJ (1988). "The colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product) and its ligand". Journal of Cell Science. Supplement. 9: 27–44. PMID 2978516.
- Stanley ER, Berg KL, Einstein DB, Lee PS, Pixley FJ, Wang Y, Yeung YG (January 1997). "Biology and action of colony--stimulating factor-1". Molecular Reproduction and Development. 46 (1): 4–10. S2CID 20846803.
- Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD (December 1992). "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". The Biochemical Journal. 288 (Pt 2): 395–405. PMID 1334406.
- Boultwood J, Rack K, Kelly S, Madden J, Sakaguchi AY, Wang LM, et al. (July 1991). "Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion". Proceedings of the National Academy of Sciences of the United States of America. 88 (14): 6176–6180. PMID 1829836.
- Roussel MF, Cleveland JL, Shurtleff SA, Sherr CJ (September 1991). "Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling". Nature. 353 (6342): 361–363. S2CID 4304762.
- Reedijk M, Liu XQ, Pawson T (November 1990). "Interactions of phosphatidylinositol kinase, GTPase-activating protein (GAP), and GAP-associated proteins with the colony-stimulating factor 1 receptor". Molecular and Cellular Biology. 10 (11): 5601–5608. PMID 2172781.
- Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER (July 1985). "The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1". Cell. 41 (3): 665–676. S2CID 32037918.
- Coussens L, Van Beveren C, Smith D, Chen E, Mitchell RL, Isacke CM, et al. (1986). "Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus". Nature. 320 (6059): 277–280. S2CID 4365127.
- Hampe A, Shamoon BM, Gobet M, Sherr CJ, Galibert F (1989). "Nucleotide sequence and structural organization of the human FMS proto-oncogene". Oncogene Research. 4 (1): 9–17. PMID 2524025.
- Visvader J, Verma IM (March 1989). "Differential transcription of exon 1 of the human c-fms gene in placental trophoblasts and monocytes". Molecular and Cellular Biology. 9 (3): 1336–1341. PMID 2524648.
- Roberts WM, Look AT, Roussel MF, Sherr CJ (November 1988). "Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes". Cell. 55 (4): 655–661. S2CID 44261532.
- Xu DQ, Guilhot S, Galibert F (May 1985). "Restriction fragment length polymorphism of the human c-fms gene". Proceedings of the National Academy of Sciences of the United States of America. 82 (9): 2862–2865. PMID 2986142.
- Sherr CJ, Rettenmier CW (1986). "The fms gene and the CSF-1 receptor". Cancer Surveys. 5 (2): 221–232. PMID 3022923.
- Le Beau MM, Westbrook CA, Diaz MO, Larson RA, Rowley JD, Gasson JC, et al. (February 1986). "Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders". Science. 231 (4741): 984–987. PMID 3484837.
- Wheeler EF, Roussel MF, Hampe A, Walker MH, Fried VA, Look AT, et al. (August 1986). "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 of Virology. 59 (2): 224–233. PMID 3525854.
- Verbeek JS, Roebroek AJ, van den Ouweland AM, Bloemers HP, Van de Ven WJ (February 1985). "Human c-fms proto-oncogene: comparative analysis with an abnormal allele". Molecular and Cellular Biology. 5 (2): 422–426. PMID 3974576.
- Lee AW, Nienhuis AW (September 1990). "Mechanism of kinase activation in the receptor for colony-stimulating factor 1". Proceedings of the National Academy of Sciences of the United States of America. 87 (18): 7270–7274. PMID 2169623.
External links
- CSF1R+protein,+human at the U.S. 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.