CSF1R_RAT
ID CSF1R_RAT Reviewed; 978 AA.
AC Q00495;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1993, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Macrophage colony-stimulating factor 1 receptor;
DE AltName: Full=CSF-1 receptor;
DE Short=CSF-1-R;
DE Short=CSF-1R;
DE Short=M-CSF-R;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene c-Fms;
DE AltName: CD_antigen=CD115;
DE Flags: Precursor;
GN Name=Csf1r; Synonyms=Csfmr, Fms;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Wistar; TISSUE=Skeletal muscle;
RX PubMed=1389227; DOI=10.3109/08977199209026928;
RA Borycki A.G., Guillier M., Leibovitch M.P., Leibovitch S.A.;
RT "Molecular cloning of CSF-1 receptor from rat myoblasts. Sequence analysis
RT and regulation during myogenesis.";
RL Growth Factors 6:209-218(1992).
RN [2]
RP FUNCTION IN BONE RESORPTION.
RX PubMed=17121910; DOI=10.1158/1535-7163.mct-05-0313;
RA Ohno H., Kubo K., Murooka H., Kobayashi Y., Nishitoba T., Shibuya M.,
RA Yoneda T., Isoe T.;
RT "A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast
RT differentiation and osteolytic bone destruction in a bone metastasis
RT model.";
RL Mol. Cancer Ther. 5:2634-2643(2006).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor
CC for CSF1 and IL34 and plays an essential role in the regulation of
CC survival, proliferation and differentiation of hematopoietic precursor
CC cells, especially mononuclear phagocytes, such as macrophages and
CC monocytes. Promotes the release of pro-inflammatory chemokines in
CC response to IL34 and CSF1, and thereby plays an important role in
CC innate immunity and in inflammatory processes. Plays an important role
CC in the regulation of osteoclast proliferation and differentiation, the
CC regulation of bone resorption, and is required for normal bone and
CC tooth development. Required for normal male and female fertility, and
CC for normal development of milk ducts and acinar structures in the
CC mammary gland during pregnancy. Promotes reorganization of the actin
CC cytoskeleton, regulates formation of membrane ruffles, cell adhesion
CC and cell migration, and promotes cancer cell invasion. Activates
CC several signaling pathways in response to ligand binding, including the
CC ERK1/2 and the JNK pathway (By similarity). Phosphorylates PIK3R1,
CC PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production
CC of the cellular signaling molecules diacylglycerol and inositol 1,4,5-
CC trisphosphate, that then lead to the activation of protein kinase C
CC family members, especially PRKCD. Phosphorylation of PIK3R1, the
CC regulatory subunit of phosphatidylinositol 3-kinase, leads to
CC activation of the AKT1 signaling pathway. Activated CSF1R also mediates
CC activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the
CC SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals
CC both via proteins that directly interact with phosphorylated tyrosine
CC residues in its intracellular domain, or via adapter proteins, such as
CC GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or
CC STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1.
CC Receptor signaling is down-regulated by protein phosphatases, such as
CC INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream
CC effectors, and by rapid internalization of the activated receptor (By
CC similarity). In the central nervous system, may play a role in the
CC development of microglia macrophages (By similarity).
CC {ECO:0000250|UniProtKB:P07333, ECO:0000269|PubMed:17121910}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence
CC of bound ligand. CSF1 or IL34 binding leads to dimerization and
CC activation by autophosphorylation on tyrosine residues (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Monomer. Homodimer. Interacts with CSF1 and IL34. Interaction
CC with dimeric CSF1 or IL34 leads to receptor homodimerization. Interacts
CC with INPPL1/SHIP2 and THOC5. Interacts (tyrosine phosphorylated) with
CC PLCG2 (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1
CC (via SH2 domain). Interacts (tyrosine phosphorylated) with FYN, YES1
CC and SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with CBL,
CC GRB2 and SLA2 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Note=The autophosphorylated receptor is ubiquitinated and
CC internalized, leading to its degradation. {ECO:0000250}.
CC -!- DOMAIN: The juxtamembrane domain functions as autoinhibitory region.
CC Phosphorylation of tyrosine residues in this region leads to a
CC conformation change and activation of the kinase (By similarity).
CC {ECO:0000250}.
CC -!- DOMAIN: The activation loop plays an important role in the regulation
CC of kinase activity. Phosphorylation of tyrosine residues in this region
CC leads to a conformation change and activation of the kinase (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylated in response to CSF1 or IL34 binding.
CC Phosphorylation at Tyr-559 is important for normal down-regulation of
CC signaling by ubiquitination, internalization and degradation.
CC Phosphorylation at Tyr-559 and Tyr-807 is important for interaction
CC with SRC family members, including FYN, YES1 and SRC, and for
CC subsequent activation of these protein kinases. Phosphorylation at Tyr-
CC 697 and Tyr-921 is important for interaction with GRB2. Phosphorylation
CC at Tyr-721 is important for interaction with PIK3R1. Phosphorylation at
CC Tyr-721 and Tyr-807 is important for interaction with PLCG2.
CC Phosphorylation at Tyr-974 is important for interaction with CBL.
CC Dephosphorylation by PTPN2 negatively regulates downstream signaling
CC and macrophage differentiation (By similarity). {ECO:0000250}.
CC -!- PTM: Ubiquitinated. Becomes rapidly polyubiquitinated after
CC autophosphorylation, leading to its degradation (By similarity).
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; X61479; CAA43706.1; -; mRNA.
DR PIR; I60321; S16385.
DR AlphaFoldDB; Q00495; -.
DR SMR; Q00495; -.
DR BindingDB; Q00495; -.
DR GlyGen; Q00495; 9 sites.
DR iPTMnet; Q00495; -.
DR PhosphoSitePlus; Q00495; -.
DR UCSC; RGD:2425; rat.
DR RGD; 2425; Csf1r.
DR InParanoid; Q00495; -.
DR PhylomeDB; Q00495; -.
DR BRENDA; 2.7.10.1; 5301.
DR Reactome; R-RNO-449836; Other interleukin signaling.
DR PRO; PR:Q00495; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:1990682; C:CSF1-CSF1R complex; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019955; F:cytokine binding; ISS:UniProtKB.
DR GO; GO:0005011; F:macrophage colony-stimulating factor receptor activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0019903; F:protein phosphatase binding; ISO:RGD.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0007411; P:axon guidance; ISO:RGD.
DR GO; GO:0008283; P:cell population proliferation; IDA:RGD.
DR GO; GO:0045217; P:cell-cell junction maintenance; ISO:RGD.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISS:UniProtKB.
DR GO; GO:0036006; P:cellular response to macrophage colony-stimulating factor stimulus; ISS:UniProtKB.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD.
DR GO; GO:0021542; P:dentate gyrus development; IMP:RGD.
DR GO; GO:0021879; P:forebrain neuron differentiation; ISO:RGD.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IBA:GO_Central.
DR GO; GO:0030097; P:hemopoiesis; ISO:RGD.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0038145; P:macrophage colony-stimulating factor signaling pathway; ISO:RGD.
DR GO; GO:0014005; P:microglia development; IMP:RGD.
DR GO; GO:0061518; P:microglial cell proliferation; ISO:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
DR GO; GO:1990138; P:neuron projection extension; IMP:RGD.
DR GO; GO:0021772; P:olfactory bulb development; ISO:RGD.
DR GO; GO:0030316; P:osteoclast differentiation; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0046488; P:phosphatidylinositol metabolic process; ISS:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; ISS:UniProtKB.
DR GO; GO:0044794; P:positive regulation by host of viral process; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:2000147; P:positive regulation of cell motility; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISO:RGD.
DR GO; GO:0120041; P:positive regulation of macrophage proliferation; ISO:RGD.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IMP:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; ISS:UniProtKB.
DR GO; GO:0045124; P:regulation of bone resorption; IMP:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR GO; GO:0032944; P:regulation of mononuclear cell proliferation; IMP:RGD.
DR GO; GO:0002931; P:response to ischemia; ISO:RGD.
DR GO; GO:0031529; P:ruffle organization; ISS:UniProtKB.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEP:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB.
DR Gene3D; 2.60.40.10; -; 5.
DR InterPro; IPR030658; CSF-1_receptor.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013151; Immunoglobulin.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR PIRSF; PIRSF500947; CSF-1_receptor; 1.
DR SMART; SM00409; IG; 5.
DR SMART; SM00408; IGc2; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 5.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50835; IG_LIKE; 4.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Disulfide bond; Glycoprotein; Immunity;
KW Immunoglobulin domain; Inflammatory response; Innate immunity; Kinase;
KW Membrane; Nucleotide-binding; Phosphoprotein; Proto-oncogene; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
FT SIGNAL 1..19
FT /evidence="ECO:0000250"
FT CHAIN 20..978
FT /note="Macrophage colony-stimulating factor 1 receptor"
FT /id="PRO_0000016767"
FT TOPO_DOM 20..515
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 516..536
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 537..978
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 24..104
FT /note="Ig-like C2-type 1"
FT DOMAIN 107..197
FT /note="Ig-like C2-type 2"
FT DOMAIN 204..298
FT /note="Ig-like C2-type 3"
FT DOMAIN 299..397
FT /note="Ig-like C2-type 4"
FT DOMAIN 398..503
FT /note="Ig-like C2-type 5"
FT DOMAIN 580..914
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 540..572
FT /note="Regulatory juxtamembrane domain"
FT /evidence="ECO:0000250"
FT REGION 794..816
FT /note="Activation loop"
FT /evidence="ECO:0000250"
FT REGION 921..957
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 923..947
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 776
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 586..594
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 614
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 544
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 559
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P09581"
FT MOD_RES 697
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 706
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 711
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 721
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 807
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 921
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P09581"
FT MOD_RES 974
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P09581"
FT CARBOHYD 45
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 73
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 302
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 335
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 389
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 410
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 449
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 478
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 491
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 42..84
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 127..177
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 224..278
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 417..483
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
SQ SEQUENCE 978 AA; 109264 MW; 0A68456EF56BC7E3 CRC64;
MELGPPLVLL LATVWHGQGA PVIEPSGPEL VVEPGETVTL RCVSNGSVEW DGPISPYWTL
DPESPGSTLT TRNATFKNTG TYRCTELEDP MAGSTTIHLY VKDPAHSWNL LAQEVTVVEG
QEAVLPCLIT DPALKDSVSL MREGGRQVLR KTVYFFSAWR GFIIRKAKVL DSNTYVCKTM
VNGRESTSTG IWLKVNRVHP EPPQIKLEPS KLVRIRGEAA QIVCSATNAE VGFNVILKRG
DTKLEIPLNS DFQDNYYKKV RALSLNAVDF QDAGIYSCVA SNDVGTRTAT MNFQVVESAY
LNLTSEQSLL QEVSVGDSLI LTVHADAYPS IQHYNWTYLG PFFEDQRKLE FITQRAIYRY
TFKLFLNRVK ASEAGQYFLM AQNKAGWNNL TFELTLRYPP EVSVTWMPVN GSDVLFCDVS
GYPQPSVTWM ECRGHTDRCD EAQALQVWND THPEVLSQKP FDKVIIQSQL PIGTLKHNMT
YFCKTHNSVG NSSQYFRAVS LGQSKQLPDE SLFTPVVVAC MSVMSLLVLL LLLLLYKYKQ
KPKYQVRWKI IERYEGNSYT FIDPTQLPYN EKWEFPRNNL QFGKTLGAGA FGKVVEATAF
GLGKEDAVLK VAVKMLKSTA HADEKEALMS ELKIMSHLGQ HENIVNLLGA CTHGGPVLVI
TEYCCYGDLL NFLRRKAEAM LGPSLSPGQD SEGDSSYKNI HLEKKYVRRD SGFSSQGVDT
YVEMRPVSTS SSDSFFKQDL DKEPSRPLEL WDLLHFSSQV AQGMAFLASK NCIHRDVAAR
NVLLTSGHVA KIGDFGLARD IMNDSNYVVK GNARLPVKWM APESILYCVY TVQSDVWSYG
ILLWEIFSLG LNPYPGILVN NKFYKLVKDG YQMAQPVFAP KNIYSIMQSC WDLEPTRRPT
FQQICFLLQE QARLERRDQD YANLPSSGGS SGSDSGGGSS GGSSSEPEEE SSSEHLACCE
PGDIAQPLLQ PNNYQFAC
