macrophage colony-stimulating factor 1 receptor; CSF-1 receptor; CSF-1-R; CSF-1R; M-CSF-R; proto-oncogene c-Fms; CD115 (CSF1R, FMS)
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Function
- protein tyrosine-kinase receptor for CSF1 & IL34
- interacts with INPPL1/SHIP2 & THOC5 (putative)
- role in regulation of survival, proliferation & differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages & monocytes
- promotes the release of proinflammatory chemokines in response to IL34 & CSF1, & thus plays a role in innate immunity & in inflammatory processes
- role in regulation of osteoclast proliferation & differentiation, regulation of bone resorption
- required for normal bone & tooth development
- required for normal male & female fertility, & for normal development of milk ducts & acinar structures in the mammary gland during pregnancy
- promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion & cell migration
- phosphorylates PIK3R1, PLCG2, GRB2, SLA2 & CBL activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol & inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD
- phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway
- activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 &/or MAPK3/ERK1, & of the SRC family kinases SRC, FYN & YES1
- activated CSF1R transmits signals both via proteins that directly interact with phosphorylated Tyr in its intracellular domain, or via adapter proteins, such as GRB2
- promotes activation of STAT family members STAT3, STAT5A &/or STAT5B
- promotes Tyr phosphorylation of SHC1 & INPP5D/SHIP-1
- receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor & its downstream effectors, & by rapid internalization of the activated receptor
- present in an inactive conformation in the absence of bound ligand
- CSF1 or IL34 binding leads to dimerization & activation by autophosphorylation on Tyr
- autophosphorylated in response to CSF1 or IL34 binding
- phosphorylation at Tyr-561 plays a role in normal down-regulation of signaling by ubiquitination, internalization & degradation
- phosphorylation at Tyr-561 & Tyr-809 plays a role in interaction with SRC family members, including FYN, YES1 & SRC, & for subsequent activation of these protein kinases
- phosphorylation at Tyr-699 & Tyr-923 plays a role in interaction with GRB2
- phosphorylation at Tyr-723 plays a role in interaction with PIK3R1
- phosphorylation at Tyr-708 plays a role in normal receptor degradation
- phosphorylation at Tyr-723 & Tyr-809 plays a role in interaction with PLCG2
- phosphorylation at Tyr-969 plays a role in interaction with CBL
- ubiquitinated
- rapidly polyubiquitinated after autophosphorylation, leading to its degradation
- interacts with INPPL1/SHIP2 & THOC5 (putative)
- interacts with CSF1 & IL34
- interaction with dimeric CSF1 or IL34 leads to receptor homodimerization
- interacts (Tyr phosphorylated) with PLCG2 (via SH2 domain)
- interacts (Tyr phosphorylated) with PIK3R1 (via SH2 domain)
- interacts (Tyr phosphorylated) with FYN, YES1 & SRC (via SH2 domain)
- interacts (Tyr phosphorylated) with CBL, GRB2 & SLA2
Inhibition:
- inhibited by imatinib/STI-571 (Gleevec), dasatinib, sunitinib/SU11248, lestaurtinib/CEP-701, midostaurin/PKC-412, Ki20227, linifanib/ABT-869, Axitinib/AG013736, sorafenib/BAY 43-9006 & GW2580
Structure
- monomer, homodimer
- the juxtamembrane domain functions as autoinhibitory region
- phosphorylation of Tyr in this region leads to a conformation change & activation of kinase actiivity
- belongs to the protein kinase superfamily, Tyr protein kinase family, CSF-1/PDGF receptor subfamily
- contains 5 Ig-like C2-type domains (immunoglobulin-like)
- contains 1 protein kinase domain
Compartment
- plasma membrane; single-pass type 1 membrane protein
Expression
- expressed in bone marrow & in differentiated blood mononuclear cells
- up-regulated by glucocorticoids
- tissue distribution:
- macrophages & precursors
- osteoclasts
- placental trophoblast
- breast tissue
- microglia
- neurons
- astrocytes
- distribution in tumors
- AML ~10%
- endometrial cancers (some)
- ovarian cancers (some)
- breast cancers (some)
- vascular smooth muscle cells in atheromas
- choriocarcinoma cells
Pathology
- deficiency associated with
- abnormal bone remodeling
- osteopetrosis
- abnormal breast development
- decreased fertility
- aberrant expression of CSF1 or CSF1R
- can promote cancer cell proliferation, invasion & formation of metastases
- overexpression of CSF1 or CSF1R is observed in some breast cancer, ovarian cancer, prostate cancer, & endometrial cancer
- may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, & allograft rejection
- can promote cancer cell proliferation, invasion & formation of metastases
- defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids
Pharmacology
- inhibited by chemotherapeutic agents:
More general terms
Additional terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/P07333.html
- ↑ http://www.pathologyoutlines.com/cd100247.html 21 June 2005
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/CSF1RID40161ch5q32.html