CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor

CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor » CSF-1 receptor;CSF-1-R; CSF-1R; M-CSF-R; Proto-oncogene c-Fms;
Hydrophobic Thickness 40.8 ± 1.2 Å
Tilt Angle 1 ± 1°
ΔGtransfer -53.2 kcal/mol
ΔGfold -30.4 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 510-539 (510-543)
Pathways

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Hematopoietic cell lineage (KEGG)

Osteoclast differentiation (KEGG)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Transcriptional misregulation in cancer (KEGG)

PDB 2i0v (538-678, A=753-922), 2i0y (538-678, A=753-922), 2i1m (538-678, A=753-922), 3bea (538-678, A=753-922), 3krj (538-678, A=753-922), 3krl (538-678, A=753-922), 3dpk (538-678, A=771-922), 3lcd (538-919), 2ogv (543-918), 3lco (550-919), 4hw7 (A=542-919), 4dkd (C=20-299), 4liq (E=2-512)
OPM 3bea
Complexes

CSF1:CSF1R_MOUSE

Interactions

CSF1, Complex: CSF1:CSF1R, PubMed

ITAV, Complex: ITAV:CSF1R, PubMed

TIE2, Complex: CSF1R:TIE2, PDBID: 3bea

Domains

AA: 207-293, PDBID: 4DKD, Subunit C, Seq Identity:100%, Immunoglobulin domain

AA: 397-489, PDBID: 4LIQ, Subunit E, Seq Identity:100%, Immunoglobulin domain

AA: 582-910, PDBID: 2I0V, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor
FUNCTION: 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. 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.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Present in an inactive conformation in the absence of bound ligand. CSF1 or IL34 binding leads to dimerization and activation by autophosphorylation on tyrosine residues. 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 and GW2580.

SUBUNIT: Interacts with INPPL1/SHIP2 and THOC5 (By similarity). Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction with dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts (tyrosine phosphorylated) with PLCG2 (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1 (via SH2 domain). Interacts (tyrosine phosphorylated) with FYN, YES1 and SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with CBL, GRB2 and SLA2.

TISSUE SPECIFICITY: Expressed in bone marrow and in differentiated blood mononuclear cells.

INDUCTION: Up-regulated by glucocorticoids.

DOMAIN: The juxtamembrane domain functions as autoinhibitory region. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase.

DOMAIN: The activation loop plays an important role in the regulation of kinase activity. Phosphorylation of tyrosine residues in this region leads to a conformation change and activation of the kinase.

DISEASE: Note=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.

DISEASE: Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.

DISEASE: Leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) OMIM: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.

UniProt features for CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor
SIGNAL 1 19 Potential.
CHAIN 20 972 Macrophage colony-stimulating factor 1 receptor.
DOMAIN 21 104 Ig-like C2-type 1.
DOMAIN 107 197 Ig-like C2-type 2.
DOMAIN 203 290 Ig-like C2-type 3.
DOMAIN 299 399 Ig-like C2-type 4.
DOMAIN 402 502 Ig-like C2-type 5.
DOMAIN 582 910 Protein kinase.
REGION 542 574 Regulatory juxtamembrane domain.
REGION 796 818 Activation loop.
ACT_SITE 778 778 Proton acceptor (By similarity).
DISULFID 42 84 By similarity.
DISULFID 127 177 By similarity.
DISULFID 224 278 By similarity.
DISULFID 419 485 By similarity.
Amino Acid Sequence for CSF1R_HUMAN » Macrophage colony-stimulating factor 1 receptor
MGPGVLLLLL VATAWHGQGI PVIEPSVPEL VVKPGATVTL RCVGNGSVEW DGPPSPHWTL YSDGSSSILS TNNATFQNTG TYRCTEPGDP LGGSAAIHLY VKDPARPWNV LAQEVVVFED QDALLPCLLT DPVLEAGVSL VRVRGRPLMR HTNYSFSPWH GFTIHRAKFI QSQDYQCSAL MGGRKVMSIS IRLKVQKVIP GPPALTLVPA ELVRIRGEAA QIVCSASSVD VNFDVFLQHN NTKLAIPQQS DFHNNRYQKV LTLNLDQVDF QHAGNYSCVA SNVQGKHSTS MFFRVVESAY LNLSSEQNLI QEVTVGEGLN LKVMVEAYPG LQGFNWTYLG PFSDHQPEPK LANATTKDTY RHTFTLSLPR LKPSEAGRYS FLARNPGGWR ALTFELTLRY PPEVSVIWTF INGSGTLLCA ASGYPQPNVT WLQCSGHTDR CDEAQVLQVW DDPYPEVLSQ EPFHKVTVQS LLTVETLEHN QTYECRAHNS VGSGSWAFIP ISAGAHTHPP DEFLFTPVVV ACMSIMALLL LLLLLLLYKY KQKPKYQVRW KIIESYEGNS YTFIDPTQLP YNEKWEFPRN NLQFGKTLGA GAFGKVVEAT AFGLGKEDAV LKVAVKMLKS TAHADEKEAL MSELKIMSHL GQHENIVNLL GACTHGGPVL VITEYCCYGD LLNFLRRKAE AMLGPSLSPG QDPEGGVDYK NIHLEKKYVR RDSGFSSQGV DTYVEMRPVS TSSNDSFSEQ DLDKEDGRPL ELRDLLHFSS QVAQGMAFLA SKNCIHRDVA ARNVLLTNGH VAKIGDFGLA RDIMNDSNYI VKGNARLPVK WMAPESIFDC VYTVQSDVWS YGILLWEIFS LGLNPYPGIL VNSKFYKLVK DGYQMAQPAF APKNIYSIMQ ACWALEPTHR PTFQQICSFL QEQAQEDRRE RDYTNLPSSS RSGGSGSSSS ELEEESSSEH LTCCEQGDIA QPLLQPNNYQ FC