CSF1R

The protein encoded by this gene is 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 the receptor kinase through a process of oligomerization and transphosphorylation. The encoded protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. Mutations in this gene have been associated with a predisposition to myeloid malignancy. The first intron of this gene contains a transcriptionally inactive ribosomal protein L7 processed pseudogene oriented in the opposite direction. [provided by RefSeq]

Colony Stimulating Factor 1 Receptor

Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathway (PubMed:20504948, PubMed:30982609).

Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and 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 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. In the central nervous system, may play a role in the development of microglia macrophages (PubMed:30982608).

Axon guidance Source: Ensembl
Cell-cell junction maintenance Source: UniProtKB
Cell population proliferation Source: UniProtKB
Cellular response to cytokine stimulus Source: UniProtKB
Cellular response to macrophage colony-stimulating factor stimulus Source: UniProtKB
Cytokine-mediated signaling pathway Source: UniProtKB
Forebrain neuron differentiation Source: Ensembl
Hematopoietic progenitor cell differentiation Source: GO_Central
Hemopoiesis Source: UniProtKB
Inflammatory response Source: UniProtKB
Innate immune response Source: UniProtKB-KW
Macrophage colony-stimulating factor signaling pathway Source: BHF-UCL
Macrophage differentiation Source: UniProtKB
Mammary gland duct morphogenesis Source: UniProtKB
Microglial cell proliferation Source: Ensembl
Monocyte differentiation Source: UniProtKB
Multicellular organism development Source: GO_Central
Negative regulation of apoptotic process Source: Ensembl
Negative regulation of cell population proliferation Source: Ensembl
Olfactory bulb development Source: Ensembl
Osteoclast differentiation Source: UniProtKB
Peptidyl-tyrosine phosphorylation Source: UniProtKB
Phosphatidylinositol-mediated signaling Source: UniProtKB
Phosphatidylinositol metabolic process Source: UniProtKB
Positive regulation by host of viral process Source: Ensembl
Positive regulation of cell migration Source: UniProtKB
Positive regulation of cell motility Source: UniProtKB
Positive regulation of cell population proliferation Source: UniProtKB
Positive regulation of chemokine production Source: UniProtKB
Positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
Positive regulation of kinase activity Source: GO_Central
Positive regulation of macrophage chemotaxis Source: ARUK-UCL
Positive regulation of macrophage proliferation Source: ARUK-UCL
Positive regulation of protein phosphorylation Source: UniProtKB
Positive regulation of protein serine/threonine kinase activity Source: UniProtKB
Positive regulation of protein tyrosine kinase activity Source: UniProtKB
Positive regulation of tyrosine phosphorylation of STAT protein Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Regulation of actin cytoskeleton reorganization Source: UniProtKB
Regulation of bone resorption Source: UniProtKB
Regulation of cell shape Source: UniProtKB
Regulation of transcription initiation from RNA polymerase II promoter Source: Reactome
Response to ischemia Source: ARUK-UCL
Ruffle organization Source: UniProtKB
Signal transduction Source: ProtInc
Transmembrane receptor protein tyrosine kinase signaling pathway Source: UniProtKB

Cell membrane

Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.
Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.
Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS):
An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.
Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS):
An autosomal recessive disease with variable manifestations. Main features are brain malformations with calcifying leukoencephalopathy, progressive neurodegeneration, and bone sclerotic features. The age at onset ranges from infancy to early adulthood. Neurologic features include loss of previous motor and language skills, cognitive impairment, spasticity, and focal seizures. Brain imaging shows periventricular white matter abnormalities and calcifications, large cisterna magna or Dandy-Walker malformation, and sometimes agenesis of the corpus callosum.

Extracellular: 20-517
Helical: 518-538
Cytoplasmic: 539-972

Autophosphorylated in response to CSF1 or IL34 binding (PubMed:24336230, PubMed:20489731, PubMed:23408870). Phosphorylation at Tyr-561 is important for normal down-regulation of signaling by ubiquitination, internalization and degradation. Phosphorylation at Tyr-561 and Tyr-809 is important for interaction with SRC family members, including FYN, YES1 and SRC, and for subsequent activation of these protein kinases. Phosphorylation at Tyr-699 and Tyr-923 is important for interaction with GRB2. Phosphorylation at Tyr-723 is important for interaction with PIK3R1. Phosphorylation at Tyr-708 is important for normal receptor degradation. Phosphorylation at Tyr-723 and Tyr-809 is important for interaction with PLCG2. Phosphorylation at Tyr-969 is important for interaction with CBL. Dephosphorylation by PTPN2 negatively regulates downstream signaling and macrophage differentiation.
Ubiquitinated. Becomes rapidly polyubiquitinated after autophosphorylation, leading to its degradation.