CSF1R_FELCA
ID CSF1R_FELCA Reviewed; 980 AA.
AC P13369;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1990, sequence version 1.
DT 03-AUG-2022, entry version 163.
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=FMS;
OS Felis catus (Cat) (Felis silvestris catus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Feliformia; Felidae; Felinae; Felis.
OX NCBI_TaxID=9685;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2849512; DOI=10.1016/0092-8674(88)90242-5;
RA Woolford J., McAuliffe A., Rohrschneider L.R.;
RT "Activation of the feline c-fms proto-oncogene: multiple alterations are
RT required to generate a fully transformed phenotype.";
RL Cell 55:965-977(1988).
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}.
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-558 is important for normal down-regulation of
CC signaling by ubiquitination, internalization and degradation.
CC Phosphorylation at Tyr-558 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 696 and Tyr-921 is important for interaction with GRB2. Phosphorylation
CC at Tyr-720 is important for interaction with PIK3R1. Phosphorylation at
CC Tyr-720 and Tyr-807 is important for interaction with PLCG2.
CC Phosphorylation at Tyr-977 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; J03149; AAA30811.1; -; mRNA.
DR PIR; A31636; TVCTMD.
DR RefSeq; NP_001009231.1; NM_001009231.1.
DR AlphaFoldDB; P13369; -.
DR SMR; P13369; -.
DR STRING; 9685.ENSFCAP00000003348; -.
DR GeneID; 493706; -.
DR KEGG; fca:493706; -.
DR CTD; 1436; -.
DR eggNOG; KOG0200; Eukaryota.
DR InParanoid; P13369; -.
DR OrthoDB; 236292at2759; -.
DR Proteomes; UP000011712; Unplaced.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:1990682; C:CSF1-CSF1R complex; IBA:GO_Central.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
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:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
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:0002244; P:hematopoietic progenitor cell differentiation; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
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:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
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:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR GO; GO:0031529; P:ruffle organization; ISS:UniProtKB.
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; 4.
DR SMART; SM00408; IGc2; 4.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 5.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50835; IG_LIKE; 3.
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 2: Evidence at transcript 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:0000255"
FT CHAIN 20..980
FT /note="Macrophage colony-stimulating factor 1 receptor"
FT /id="PRO_0000016764"
FT TOPO_DOM 20..514
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 515..535
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 536..980
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 21..100
FT /note="Ig-like C2-type 1"
FT DOMAIN 107..197
FT /note="Ig-like C2-type 2"
FT DOMAIN 202..297
FT /note="Ig-like C2-type 3"
FT DOMAIN 299..397
FT /note="Ig-like C2-type 4"
FT DOMAIN 400..499
FT /note="Ig-like C2-type 5"
FT DOMAIN 579..908
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 539..571
FT /note="Regulatory juxtamembrane domain"
FT /evidence="ECO:0000250"
FT REGION 723..743
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 794..816
FT /note="Activation loop"
FT /evidence="ECO:0000250"
FT REGION 918..959
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 918..950
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 585..593
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 613
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 543
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 558
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P09581"
FT MOD_RES 696
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 705
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 710
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P07333"
FT MOD_RES 720
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 977
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 94
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 153
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 275
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 286
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 410
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 477
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 490
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..482
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
SQ SEQUENCE 980 AA; 108507 MW; 4E5CF661E97CFCFF CRC64;
MGPRALLVLL VATAWHAQGV PVIQPSGPEL VVEPGTTVTL RCVGNGSVEW DGPISPHWNL
DLDPPSSILT TNNATFQNTG TYHCTEPGNP QGGNATIHLY VKDPARPWKV LAQEVTVLEG
QDALLPCLLT DPALEAGVSL VRVRGRPVLR QTNYSFSPWH GFTIHKAKFI ENHVYQCSAR
VDGRTVTSMG IWLKVQKDIS GPATLTLEPA ELVRIQGEAA QIVCSASNID VNFDVSLRHG
DTKLTISQQS DFHDNRYQKV LTLNLDHVSF QDAGNYSCTA TNAWGNHSAS MVFRVVESAY
LNLTSEQSLL QEVTVGEKVD LQVKVEAYPG LESFNWTYLG PFSDYQDKLD FVTIKDTYRY
TSTLSLPRLK RSEAGRYSFL ARNAGGQNAL TFELTLRYPP EVRVTMTLIN GSDTLLCEAS
GYPQPSVTWV QCRSHTDRCD ESAGLVLEDS HSEVLSQVPF HEVIVHSLLA IGTLEHNRTY
ECRAFNSVGN SSQTFWPISI GAHTQLPDEL LFTPVLLTCM SIMALLLLLL LLLLYKYKQK
PKYQVRWKII ESYEGNSYTF IDPTQLPYNE KWEFPRNNLQ FGKTLGAGAF GKVVEATAFG
LGKEDAVLKV AVKMLKSTAH ADEKEALMSE LKIMSHLGQH ENIVNLLGAC THGGPVLVIT
EYCCYGDLLN FLRRQAEAML GPSLSVGQDP EAGAGYKNIH LEKKYVRRDS DFSSQGVDTY
VEMRPVSTSS SNDSFSEEDL GKEDGRPLEL RDLLHFSSQV AQGMAFLASK NCIHRDVAAR
NVLLTSGRVA KIGDFGLARD IMNDSNYIVK GNARLPVKWM APESIFDCVY TVQSDVWSYG
ILLWEIFSLG LNPYPGILVN SKFYKLVKDG YQMAQPAFAP KNIYSIMQAC WALEPTRRPT
FQQICSLLQK QAQEDRRVPN YTNLPSSSSS SSSSSSSCRT GSGGGSSSEP EEESSSEHLA
CCEQGDIAQP LLQPNNYQFC
